747

Martin Paul, Ali Poyan Mehr and Reinhold Kreutz
Physiol Rev 86:747-803, 2006. doi:10.1152/physrev.00036.2005
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Physiol Rev 86: 747– 803, 2006;
doi:10.1152/physrev.00036.2005.
Physiology of Local Renin-Angiotensin Systems

MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin,

Charité-University Medicine Berlin, Berlin, Germany
I. Local Renin-Angiotensin Systems 747

A. Definition of local RAS 747
B. Components of the local RAS 748
II. Localization and Functional Aspects 752

A. Heart 752
B. Vasculature 756
C. Nervous system 760
D. Reproductive tract 767
E. Skin 773
F. Digestive organs 774
G. Sensory organs 776
H. Lymphatic tissue 777
I. Adipose tissue 778
III. Prenatal Development 779
IV. Summary 783
Paul, Martin, Ali Poyan Mehr, and Reinhold Kreutz. Physiology of Local Renin-Angiotensin Systems. Physiol
Rev 86: 747– 803, 2006; doi:10.1152/physrev.00036.2005.—Since the first identification of renin by Tigerstedt and
Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system
is characterized by an increased complexity, as evidenced by the discovery of new functional components and
pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus
of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin
(ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal
diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an
important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on
the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions.
Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body
of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological
effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation,
but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be
important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and
knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal
development. Taken together, these findings may become increasingly important in the study of organ physiology
but also for a fresh look at the implications of these findings for organ pathophysiology.
I. LOCAL RENIN-ANGIOTENSIN SYSTEMS that is secreted from the juxtaglomerular apparatus of the
kidney (245, 250, 540, 631) to form the decapeptide an-
A. Definition of Local RAS giotensin (ANG) I. ANG I is then activated to the octapep-
tide ANG II by angiotensin converting enzyme (ACE), a
In its “textbook” definition, the renin-angiotensin sys- membrane-bound metalloproteinase, which is predomi-
tem (RAS) is a peptidergic system with endocrine char- nantly expressed in high concentrations on the surface of
acteristics. The substrate of the system, angiotensinogen, endothelial cells in the pulmonary circulation (109, 111,
an ␣-glycoprotein, is released from the liver (152, 250, 250, 486, 664, 665, 767). ANG II, considered the main
444) and is cleaved in the circulation by the enzyme renin effector peptide of the RAS, is then acting on specific
www.prv.org 0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society 747
748 MARTIN PAUL, ALI POYAN MEHR, AND REINHOLD KREUTZ
receptors, for example, to induce vasoconstriction by cardiac renin were based on artifacts due to contamina-
interacting with ANG receptors on vascular smooth mus- tion with plasma renin or active renin uptake from the
cle cells or by stimulating the release of aldosterone from circulation. This issue should not threaten the concept of
the adrenal cortex (250, 285, 562). local RAS, since either mechanism could contribute to
This view of the RAS, which has been generated by local ANG synthesis and actions. Modern concepts of the
accumulated evidence over decades, had to be expanded tissue RAS, therefore, are function oriented.
significantly by more recent findings that increased the
complexity of the system. Different ANG receptors (AT1,
B. Components of the Local RAS
AT2, AT4) and signal transduction pathways involved have
been characterized (142, 306, 462, 505, 604, 639, 681, 691,
The characteristics and regulatory significance of
712, 724, 785). Moreover, additional truncated peptides
long-known components of the tissue RAS such as renin,
such as ANG-(1O7) have been identified (200, 310, 420,
angiotensinogen, ACE, and ANG peptides (ANG I and II)
595, 769), and alternative pathways of ANG II formation,
have been reviewed extensively (27, 172, 177, 381, 415,
for example, by the serine protease chymase (which can
482, 527, 727) and will not be addressed further in this
also cleave ANG I to form ANG II), have been proposed
section. The focus of this section is set rather on recent
(20, 728, 730, 781).
discoveries concerning new factors and pathways in-

The resulting change of our view of the RAS has been
volved in ANG biosynthesis and function.
the introduction of the concept of “local” or “tissue” renin
angiotensin systems (178, 415, 527). This concept was
1. Prorenin and renin binding and receptors
based on findings of RAS components in “unlikely” places
(such as the “kidney enzyme” renin in the brain) where The binding of prorenin and renin to the cell surface
the endocrine actions of the system could not explain the in tissues is of pivotal importance with regard to the
findings (219, 220). This in turn led to new hypotheses and physiology of local RAS at the tissue level in organs, since
functional concepts of local RAS actions based on the it provides a mechanism to generate ANG II locally in
tissue-based synthesis of ANG II. It is not surprising that excess of the ANG II that is produced in plasma. Previ-
the notion of tissue-based RAS with independent actions ously, it was suggested that binding of prorenin and/or
was not received with great enthusiasm, but rather led to renin is responsible for uptake into tissues (5). It was
significant controversies on the subject. Nevertheless, the postulated that this mechanism (which is known also for
database on local RAS accumulated so far has by and other enzymes) rather than de novo renin biosynthesis at
large been convincing and strengthened by two major obscure local sites is responsible for local actions of ANG
technical advances, namely, the use of molecular biology II. Our understanding of the potential role of prorenin and
and the availability of transgenic and knock-out models renin binding has been significantly expanded by the char-
with altered expression of RAS components (28, 31, 106, acterization of several proteins capable of binding prore-
370, 377, 534, 537, 696). nin and/or renin (87, 315, 488, 490).
The genes for all components of the RAS have been The mannose-6-phosphate receptor (M6P) has been
cloned, and gene expression studies could verify their shown to be involved in renin and prorenin uptake into
mRNA expression and regulation in many tissues, dem- cells (132, 602, 733, 737). The cation-independent M6P is
onstrating the possibility of local ANG II synthesis. Over- directly coupled to G proteins (225, 603) and binds not
expression of RAS genes in transgenic mice and rats as only prorenin and renin but is in general involved in
well as the knock-out of these genes in mice have allowed transport of proteins containing M6P residues; it leads
detailed studies on the function of local RAS (28, 31, 106, also to insulin-like growth factor II internalization and
370, 376, 534, 537, 696). It has also become increasingly inactivation (225). M6P was shown to bind renin and
clear that these systems are not isolated entities but can prorenin on neonatal rat cardiac myocytes (601) and on
interact with the endocrine RAS as well as other peptide human endothelial cells (5). Only glycosylated prorenin
systems (such as the endothelin system) on multiple lev- and renin are bound by this receptor, and binding is
els (538, 582, 585, 614). followed by internalization and activation by proteolytic
The early controversy on the novel concept of tissue cleavage and subsequent immediate degradation of renin
RAS has been based on the question of local synthesis as demonstrated on cardiac cells (488, 601). Particularly
versus uptake from the circulation. A case in point repre- studies in endothelial cells indicated that uptake of pro-
sents the controversy between investigators after the renin by M6P represents a clearance mechanism (733).
demonstration of renin expression in the heart (178, 415) The role as a clearance receptor on cardiac myocytes is
and those questioning local renin synthesis (751). This also supported by the finding that intracellular ANG gen-
controversy was based on the fact that detection of renin eration could not be demonstrated following (pro)renin
mRNA in the heart could only be demonstrated inconsis- uptake in these cells (315, 603). In addition, Peters et al.
tently, leading to the suggestion that studies measuring (542) provided evidence for the existence for a prorenin
Physiol Rev • VOL 86 • JULY 2006 • www.prv.org

PHYSIOLOGY OF LOCAL RENIN-ANGIOTENSIN SYSTEMS 749
binding protein on cardiac cells that is different from the ceptor is not only important for regulating the activity of
M6P receptor. The functional significance of prorenin the system but also in the mediation of signal transduc-
internalization in cardiomyocytes was shown in vitro and tion processes, for example, in brain development and
in vivo, supporting the concept of an intracrine RAS in cognitive function (568).
these cells (488, 542). In the regulation of the RAS it is well established that
It has also been suggested that proteins interacting prorenin represents the inactive precursor of renin that
with renin could act as renin inhibitors in vivo, such as a does not proteolytically self-activate like, for instance,
renin binding protein (RnBP) which was isolated from the pepsinogen (689). This phenomenon has been attributed
porcine kidney (698) and identified in porcine, rat, and to the prosegment with its 43 residues attached to the NH2
human tissues (693, 697, 698). Originally, RnBP was iden- terminus of mature renin that prevents interaction with
tified as a protein in the kidney that was capable of angiotensinogen and thus cleavage of ANG I (40, 267,
binding renin in renal homogenates giving rise to a com- 650). While earlier in vitro studies have suggested that
plex designated high-molecular-weight renin (698). Sub- prorenin can be activated by endopeptidases such as
sequently, RnBP was shown to be identical to the N-acyl- trypsin and cathepsin B or by nonproteolytic mechanisms
D-glucosamine 2-epimerase (437, 699). The gene encoding such as by low pH (245, 465, 689), the mechanisms in-
RnBP has been mapped on chromosome X (697), and volved in prorenin activation in vivo and their physiolog-

chromosomal fine-mapping in the rat indicated that this ical role are still not fully characterized (689). More re-
locus does not fall within a blood pressure quantitative cently, studies using specific antibodies designed from the
trait locus previously identified in rat models of hyperten- tertiary structure of prorenin have shown that there is an
sion (812). Moreover, knock-out of the gene encoding for essential region in the NH2-terminal region of prorenin,
this protein in mice did not show any effects on RAS which is responsible for the nonproteolytic form of acti-
activity or blood pressure (621), suggesting that RnBP is vation (689). Suzuki et al. (689) have demonstrated two
of little functional significance in this context. key segments in this region termed the “gate” and “han-
In contrast to these negative studies, a specific hu- dle” regions. Subsequent studies (296) have further shown
man renin receptor has been recently identified by expres- that specific binding proteins, interacting with the “han-
sion cloning (490). The complementary DNA of this renin dle” region, are responsible for the nonproteolytic activa-
receptor encodes a 350-amino acid protein with a single tion of prorenin through the induction of a conforma-
transmembrane domain and no homology to any known tional change. These findings shed new light on earlier
membrane protein (490). High expression levels are de- observations of an independent functional role of prore-
tected in the heart, brain, and placenta at the mRNA level, nin, suggesting that prorenin is a useful marker of diabetic
while lower levels are observed in the kidney and liver microvascular complications (143, 423, 481) and Wilm’s
(488, 490). tumor (379).
This 45-kDa membrane protein binds both prorenin In the kidney it has been suggested that prorenin
and renin and shows a dual function (488). First, binding uptake and intrarenal activation of the kidney RAS is
of prorenin activates cellular effects that are independent responsible for inducing renal damage and microvascular
from ANG II generation by activating the mitogen-acti- changes (296). Interestingly, an earlier transgenic study
vated protein (MAP) kinases p(42)/p(44) and extracellular has come to similar conclusions using a reverse approach
signal-regulated kinases (ERK) 1/2 (488, 490). Second, this (740). Overexpression of prorenin, subjected to site-di-
receptor acts as a cofactor by increasing the efficiency of rected mutagenesis at its proteolytic cleavage site in
ANG I generation on the cell surface by receptor-bound transgenic rats, has led to high prorenin levels in the
prorenin and renin (488, 490). Additional studies showed plasma, but also to a severe renal phenotype character-
that the receptor is localized in the kidney in the mesan- ized by severe nephrosclerosis in the absence of elevated
gium and in the subendothelium of renal, uterine, and blood pressure (740). Now that the mechanisms of non-
cardiac blood vessels (488, 490). Nguyen and co-workers proteolytic activation of prorenin appear to be deci-
(487, 489) demonstrated that renin can bind to this recep- phered, this could finally solve the controversy of ele-
tor in human mesangial cells in culture and that binding vated prorenin levels and cardiovascular phenotypes not
induces hypertrophic effects and an increase of plasmin- only in the kidney but also in other organs such as the
ogen activator inhibitor-1. Renin bound to this receptor heart (542). The proposed mechanism could be the basis
was neither internalized nor degraded (487, 489). The for the understanding of these phenomena and provide
gene encoding for this renin receptor, i.e., ATP6AP2, new insights into the function of intracellular RAS and
maps to the X chromosome and was recently linked to their independence from the regulation of active renin in
familial X-linked mental retardation and epilepsy syn- the plasma. The identification of this receptor could play
drome (568). This clinical phenotype is caused by a an important role for the understanding of cellular effects
unique exonic splice enhancer mutation in ATP6AP2, of prorenin/renin regulation of cell-specific ANG II forma-
suggesting that the interaction between renin and its re- tion. It is likely that this discovery could change our view

of tissue RAS function by defining an independent func- tive angiotensin peptides in particular by the conversion
tional role for prorenin and renin that are independent of ANG II to ANG-(1O7) and ANG I to ANG-(1O9) (169,
from the effects of ANG II (and other peptides) generated 741). Thus, while ACE generates ANG II from ANG I
within the classical RAS cascade. Yet, the function, rele- through cleavage of the COOH-terminal dipeptide His-
vance, and tissue specificity of the renin receptor and Leu, ACE2 catalyzes the conversion of ANG II into ANG-
other potential pro(renin) binding mechanisms are still (1O7) by removing the COOH-terminal amino acid phe-
poorly defined, and future research has to investigate nylalanine. In addition, ACE2 can cleave the COOH-ter-
whether these sites function alone, together, or in com- minal residue of the decapeptide ANG I, thus generating
bination with other mechanisms at the tissue level (87). the nonapeptide ANG-(1O9), which may be subsequently
converted to ANG-(1O7) by ACE. ACE2 can also cleave
2. ANG-(1O7) des-Arg(9)-bradykinin but does not hydrolyze bradykinin
and is insensitive to ACE inhibitors (169, 713, 741). The
Alternative cleavage products of ANG I have been
fact that ACE2 generates the vasodilator ANG-(1O7) can
suggested as functional peptides in the RAS (200, 201, 595,
be viewed as a further counterbalancing tissue-specific
596). The most extensively studied of these is
mechanism within the activated RAS.
ANG-(1O7), which is generated by the action of several
The expression of ACE2 is (in comparison with

ACE-independent enzymes from ANG I (200). Some of
these enzymes such as neprylisin are also involved in the ACE) relatively restricted to cardiac blood vessels and
metabolism of atrial natriuretic factors and bradykinin, tubular epithelia of the kidneys, which together with its
and ACE has been shown to be active in metabolism and differential enzyme activity might suggest a distinctive
breakdown of ANG-(1O7), suggesting a complex interac- physiological function blood pressure and volume reg-
tion between different cardiovascular peptide systems ulation (128, 713). A recent study (119) has mapped
(769). ANG-(1O7) has multiple actions that are mostly ACE2 to a region on the X chromosome that is thought
counteracting those described for ANG II (201, 310, 420, to be involved in the genetic modulation of hyperten-
596). sion (271, 794, 812). However, a potential role of ACE2
for genetic hypertension appears questionable since the
3. ACE and ACE2 reported expression analysis of ACE2 in hypertensive
rat strains (119) was at variance with the allelic effects
Recently, a novel functional role of ACE involving at the blood pressure loci observed in mapping analysis
outside-in signaling has been identified by Fleming and with these strains (271, 794, 812). Crackower et al.
co-workers (208, 353–355). They demonstrated that ACE (119) performed a number of knock-out studies in mice
inhibitor binding to ACE activates ACE-associated casein and Drosophila, and while there were only modest
kinase 2 (CK2)-mediated phosphorylation of ACE Ser- effects on blood pressure in mice, the genetic manipu-
1270 (355). Depending on initial phosphorylation, ACE- lation resulted in severe changes in cardiac contractil-
associated c-Jun NH2-terminal kinase (JNK) becomes ac- ity, combined with increases of cardiac ANG II levels
tivated, most likely via ACE-associated mitogen-activated and the induction of gene pathways mediating the re-
protein kinase kinase 7 (MKK7), leading to an accumula- sponse to hypoxia (119). Therefore, it has been sug-
tion of phosphorylated c-Jun in the nucleus and enhance- gested that ACE2 is important as a regulator of heart
ment of the DNA-binding activity of activator protein-1
function and development. Further expression studies
(AP-1, c-Jun dimer) (353). AP-1 activation influences en-
of ACE2 on the mRNA and protein level extended the
dothelial gene expression, i.e., increases ACE as well as
spectrum of organs in which this enzyme is expressed
cyclooxygenase-2 (COX-2) expression (354). Thus it was
(251, 251, 257) and particularly demonstrated that
shown that binding of an ACE inhibitor to ACE leads to
activation of signal events that are likely to affect the ACE2 is abundantly present in humans in the epithelia
expression of several proteins (208). The characterization of the lung and small intestine (251). However, taken
of the novel signaling pathway via ACE also suggests that together, no clear picture of the tissue distribution of
some of the beneficial effects of ACE inhibitors can be ACE2 expression and the physiological role assigned to
attributed to the activation of a distinct ACE signaling ACE2 has been yet obtained. Interestingly, work in cell
cascade rather than to the changes in ANG II and brady- lines suggested that ACE2 is the functional receptor for
kinin levels (208). coronavirus associated with the acute respiratory syn-
ACE2 represents a zinc metalloprotease with car- drome, i.e., SARS-CoV (408, 789). The functional role
boxypeptidase activity that shares ⬃42% identity with the for ACE2 for SARS-CoV replication in vivo was subse-
catalytic site of somatic ACE and can be shed from cells quently confirmed in mice (364). Additional studies
by cleavage NH2-terminal to the transmembrane domain could demonstrate that ACE2 protects against lung
(169, 713). ACE2 is involved in the generation of alterna- injury caused by SARS-CoV and other agents (301, 364).

4. N-acetyl-Ser-Asp-Lys-Pro ANG II such as vasoconstriction and aldosterone release

are mediated by the AT1 receptor, the AT2 receptor has
It is well-known that ACE is acting on several sub-
been considered to be more of an enigma (403, 724). It
strates such as ANG I and bradykinin. One of these,
appears to play an important functional role in prenatal
N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), is a hematopoetic
development, and in the adult, AT2-mediated actions have
factor that is a natural substrate for the NH2-terminal
been shown to counteract AT1 effects such as cell prolif-
domain of ACE (573). The breakdown of Ac-SDKP can be
eration in vitro (681) and in vivo (462). Increasing evi-
blocked by ACE inhibitor treatment resulting in an in-
dence supports a role of AT2 particularly in the regulation
crease of its plasma levels, and it has been suggested that
of growth, differentiation, and regeneration of neuronal
measurement of Ac-SDKP could be a marker for the clin-
tissue (676). The existence of an additional ANG receptor
ical efficiency of ACE inhibition (25). In the hematopoetic
system, Ac-SDKP acts on the cell cycle and prevents the termed AT4 has been postulated, which is interacting with
activation of pluripotent stem cells (26), and levels of a truncated ANG peptide, ANG IV or ANG-(3O8) (66, 89,
Ac-SDKP have recently been associated with anemia in 691, 785). Thus the AT4 receptor was originally defined as
heart failure patients treated with ACE inhibitors (734). the specific, high-affinity binding site for the hexapeptide
Although its relevance for cardiovascular regulation still ANG IV. Subsequently, the peptide LVV-hemorphin 7 was
remains unclear, accumulating data indeed support a also demonstrated to be a bioactive ligand of the AT4

functional role of Ac-SDKP (554, 555, 569, 761, 800).These receptor (453). The AT4 binding site has been found in
functions might include the stimulation of angiogenesis heart, vascular smooth muscle, kidney, colon, adrenal
(761) and particularly antifibrotic effects that could point gland, prostate, and many brain regions in processing
to possible effects in repair and remodeling processes in sensory and motor function (66, 89, 255, 691, 785).
the cardiovascular system (554, 555, 569, 761, 800) and Two additional novel mechanisms of ANG receptor
kidney (88, 646, 744). binding leading to contrasting effects have been recently
demonstrated (1, 140, 141, 756). First, AbdAlla et al. (1)
5. Chymase reported that the AT2 receptor can directly bind to the
AT1 receptor and thereby antagonizes the function of AT1.
An ANG II-forming serine protease termed human It was shown that heterodimerization between both re-
heart chymase has been postulated as an activator in an ceptors led to inhibition of AT1 signaling that was inde-
alternative pathway of ANG II formation in the heart (728, pendent of AT2 receptor activation (1). Second, activation
730). It is not affected by ACE inhibition and has been of AT1 receptor by autoantibodies in women with pre-
suggested as relevant for alternative pathways of ANG II eclampsia was demonstrated (756). These stimulatory au-
generation (728, 730, 781). Although several other alter- toantibodies are directed against the second extracellular
native enzymes involved in ANG II formation had been AT1 receptor loop and are capable of inducing PKC-me-
described previously such as cathepsins and tonin, chy- diated effects in vascular smooth muscle cells (756). Al-
mase deserves special attention due to its high substrate though both mechanisms have not been proven with cer-
specificity. The enzyme is also expressed in the vascular tainty and confirmed by independent groups, they opened
wall, where it has been suggested as a possible player in new arenas for future research regarding ANG receptor
ANG II-mediated arteriosclerosis (20). Although its ulti-
activation and inhibition.
mate relevance for the cardiac RAS remains to be deter-
mined, since its cellular localization is largely restricted to
mast cells (418, 728), experimental studies with selective 6. Mas
chymase inhibitors in animal models of heart diseases
The Mas protooncogene is characterized as a G pro-
have thus far generated promising results (167, 700).
tein-coupled receptor originally described as a factor in-
volved in tumorigenesis. It has been suggested that Mas is
6. Angiotensin receptors a functional ANG receptor (311), a hypothesis which has
The actions of ANG II are mediated predominantly by been challenged since binding of ANG II to cells express-
two seven transmembrane domain receptors termed AT1 ing Mas could not be shown, suggesting that it is only
and AT2 showing a complex pattern of regulation and indirectly involved in ANG II signal transduction. Exper-
function (142, 306, 336, 462, 604, 639, 681, 712, 724, 725, iments on Mas knockout mice have indeed shown a func-
785). In rat and mouse, two AT1 subtypes have been tional interaction between Mas and the AT1 receptor
cloned and characterized; they are termed AT1A and AT1B (750). This interaction may be attributable to heterooli-
(302). The AT1 and AT2 subtypes show similar properties gomerization between Mas and the AT1 receptor and lead-
of ANG II binding but different genomic structure and ing to inhibition of ANG II effects mediated by AT1 (359).
localization as well as tissue-specific expression and reg- It remains to be determined, however, whether the pro-
ulation (142). Whereas most of the well-known actions of posed effects mediated by ANG-(1O7) or other ANG pep-

FIG. 1. The renin-angiotensin system

(RAS) in the heart. Renin and angio-
tensinogen (AOGEN) are mostly taken
up from the plasma or formed locally.
Mast cell production of human heart chy-
mase may present an alternative path-
way. ANG II synthesis occurs extracellu-
larly and acts on cell-specific receptors
on different cell types such as cardiomy-
ocytes and fibroblasts.

tides via Mas could indeed be of functional relevance in not discuss the RAS in kidney and adrenal gland as these
vivo (597). have been extensively reviewed elsewhere (28, 59, 76,
259, 318, 343, 373, 376, 401, 425, 450, 473, 627, 652), and we
rather focus on local RAS in other organs that are not
II. LOCALIZATION AND FUNCTIONAL ASPECTS
typically associated with ANG formation.
Whereas many previous studies on localization and
function of tissue or local RAS have focused on their A. Heart
pathophysiological relevance, many new aspects of a
physiological role for these systems have been uncovered. The existence and function of a specific cardiac RAS
Cloning of all relevant RAS genes as well as the establish- has been a matter of debate since it has been difficult to
ment of transgenic and knock-out models have enhanced differentiate the effects of intracardiac ANG II generation
this knowledge significantly. It appears likely that local from actions by plasma-borne ANG II. Nevertheless, it has
and systemic actions of the RAS have to be integrated in become quite clear that cardiac actions of drugs inhibiting
a concerted action of ANG-mediated effects. In addition, ANG II actions such as ACE inhibitors and ANG II recep-
an independent function of local RAS (for example, in the tor blockers are in part explained by local effects at the
brain where the RAS components are also expressed in cellular level, for example, on cardiac remodeling. The
regions inside the blood-brain barrier) has been postu- predominant physiological role of the cardiac RAS ap-
lated. The most significant contribution of the locally pears to be the maintenance of an appropriate cellular
acting systems is their function at the cellular level. In this milieu balancing stimuli inducing and inhibiting cell
context, paracrine and autocrine effects appear of partic- growth and proliferation as well as mediating adaptive
ular importance, which mediate cell specific effects on responses to myocardial stress, for example, after myo-
cell growth, proliferation, and metabolism. There have cyte stretch. A schematic representation of cardiac ANG
also been some suggestions of intracellular or intracrine pathways is shown in Figure 1.
RAS actions (175) mediated by ANG binding in the cell
nucleus (704). Nevertheless, this intracellular concept of 1. Renin
ANG II synthesis and function awaits final confirmation.
The purpose of this review is to integrate aspects of The existence and relevance of cardiac renin expres-
localization of local RAS components with function and sion has been a matter of controversial debates, although
will focus predominantly on the physiological rather than some investigators have been able to detect renin mRNA
pathophysiological implications of these findings. In some in the heart by Northern blotting (174), solution hybrid-
instances, pathophysiological concepts will be used to ization assays (531), and RT-PCR (532) in various species.
enhance understanding of their physiological basis. We do Renin mRNA expression in all of these studies, however,

was rather low, and very high amounts of mRNA or total circulation (134) either due to nonspecific uptake (diffu-
RNA had to be used to bring the renin signal to the level sion) into the cellular interstitium (144, 315, 542) or
of detection. Other investigators challenged these findings through the actions of specific functional binding sites or
and were unable to find proof for local mRNA expression receptor for prorenin and renin (87, 488, 490, 541). The
in the literature (751), claiming that the measurement of M6P receptor has been shown to bind prorenin and renin
cardiac renin mRNA was based on contamination prob- cells on cardiomyocytes (601, 603). Hypertrophy of iso-
lems and artifacts. This was supported by findings that lated neonatal cardiomyocytes in culture and increase in
cultured cardiomyocytes or fibroblasts did not synthesize protein synthesis were only detected during coincubation
renin. Ultimate proof of the presence of local renin syn- of prorenin with angiotensinogen, while prorenin binding
thesis in the heart was to be expected by transgenic alone had no effect (603). The effects of prorenin plus
overexpression using the native renin promoter. Trans- angiotensinogen were comparable to those of 100 nM
genic mice carrying a genomic human renin construct
ANG II, although the ANG II levels in the medium during
showed no cardiac renin expression (798), whereas trans-
exposure of the cells to prorenin plus angiotensinogen
genic rats carrying a genomic construct of the mouse
were ⬍1 nM. This suggests that cardiac ANG II generation
Ren-2 gene under control of its own promoter expressed
by circulating renin occurs predominantly on the cell
high levels of renin mRNA in the heart (549). This sug-
surface (315, 603). In addition, the newly identified pro-

gests that at least in some species, the heart is a site of
extrarenal renin production. Other authors have sug- renin and renin receptor that is capable of activating
gested that, whereas renin is not synthesized in the heart signal transduction via MAP and ERK kinases indepen-
under physiological conditions, renin gene expression dently from ANG II generation shows high expression
may be turned on in pathophysiological situations (147). levels in the heart (488, 490). Taken together, these find-
It is interesting to note in this context that an additional ings support the concept that the physiological role of the
truncated renin mRNA has been described in heart tissue tissue RAS in the heart depends on the assembly of pro-
which lacks the prefragment of preprorenin and results in renin and renin binding receptors including M6P and ANG
the formation of a truncated prorenin protein termed receptors (488, 603). This favorable microenvironment
exon 1A renin (103, 541). The initial characterization of would allow maximal efficiency of local ANG II genera-
this isoform in rat adrenocortical cells revealed that this tion, i.e., immediate binding of ANG II to its receptors
alternative transcript encodes for a truncated prorenin with minimal loss into the extracellular space (315, 488,
that is imported into mitochondria (104). Subsequent 603).
studies demonstrated the expression of this truncated A recent study could show that unglycosylated renin
isoform in the rat heart and suggested that only this is rapidly taken up by cardiomyocytes by a mechanism
alternative renin transcript but not the full-length isoform that is independent from the M6P receptor and that trans-
is expressed in the rat heart (103, 541, 542). This conclu- genic rats with overexpression of the mouse Ren-2 gene
sion was based on studies in which renin expression was (which have high prorenin levels in the plasma) exhibit
analyzed by a sensitive nested RT-PCR method allowing strongly enhanced intracellular levels of unglycosylated
the differentiation between the full-length transcript cod- renin in their hearts (542).
ing for preprorenin and the transcript coding for the
truncated intracellular isoform (103, 541, 542). While the
latter was detected in various rat tissues in parallel with 2. ACE
the full-length mRNA, the exon 1A renin was the only
The existence of local ACE production in the heart is,
transcript of the renin gene expressed in the heart (103,
in contrast to the renin, no matter of controversy. Cardiac
541, 542). Moreover, it was shown that in disease states
ACE mRNA can be easily detected by a number of meth-
such as cardiac hypertrophy or myocardial infarction,
ods in rat (277, 362, 626) and human hearts (532). ACE
there is no expression of the mRNA coding for the full-
length preprorenin but exclusively the exon 1A renin activity is also readily detectable, for example, by autora-
transcript is increased (103, 542). The recent findings on diography (796) or enzymatic assay (278, 362, 726). Im-
the differential regulation of preprorenin, i.e., the classi- munohistochemistry has been used to localize the pre-
cal full-length renin, and exon 1A truncated renin in the dominant source of ACE expression in cardiac blood
heart might explain some of the previous controversies vessels and the endocardium (190), whereas mRNA stud-
and discrepancies in the literature regarding renin expres- ies on cultured cardiac cells also found ACE expression in
sion in the heart, since investigators were unable to dif- cardiomyocytes (536). These studies have been confirmed
ferentiate between the two isoforms before the identifi- by expression studies showing that ACE is present in
cation of exon 1A renin (541). viable human cardiomyocytes after myocardial infarction
Less controversial is the evidence for the presence of (284). ACE2 expression has also been demonstrated in
renin protein in the heart attributed to uptake from the the heart in both animals (119, 713) and humans (67, 238).

3. Chymase tissue levels of endogenous as well as the radiolabeled

peptides. The results of this study indicated that ⬎90% of
Human heart chymase activates ANG I to ANG II but
cardiac ANG I is synthesized locally in the heart and that
is not inhibited by ACE inhibitors and could act as an
⬎75% of cardiac ANG II is synthesized locally, most of it
activator for alternative pathways of ANG II formation.
using local ANG I generation as a basis. These findings
Using whole heart homogenates, Urata et al. (729) de-
clearly show the local synthesis of ANG peptides in the
scribed that up to 80% of ANG II forming activity in the
heart as a relevant mechanism and point out that the
heart was due to chymase, while only 11% was based on
concept of a cardiac RAS is not dependent on the local
ACE activity, suggesting an increased importance of the
synthesis of angiotensinogen and renin.
chymase pathway in the human heart. When comparing
studies in humans and animals, it is important to consider
5. Angiotensin receptors
the important species differences in the pathways of in-
tracardiac ANG II generation (30). In this regard, chymase Both the AT1 and the AT2 receptors are expressed in
predominates over ACE activity in human heart, account- the heart where they appear to be localized on cardiomy-
ing for considerably higher total ANG II formation in ocytes (28, 55, 577, 590, 729). On cardiac fibroblasts, the
human heart compared with dog, rat, rabbit, and mouse receptor population appears to be dependent from the
hearts (30). The ultimate functional importance of a chy- presence or absence of cardiac disease. Normal fibro-

mase-dependent pathway of ANG II formation in the heart blasts express AT1 only but can recruit the AT2 receptor
remains questionable due to a number of factors: 1) clin- under certain pathological conditions (118, 510, 635). The
ically, ACE inhibitors are extremely efficient in the treat- function of the two ANG receptors in the heart has been
ment of cardiac disease; 2) under experimental condi- seen in perspective of a “Ying-Yang” principle, meaning
tions, most of the ANG II generated by intact cardiac that the AT1 is a stimulator of hypertrophy and prolifera-
blood vessels can be blocked by ACE inhibitors; and 3) tion of cardiac cells, whereas AT2 is mediating the oppo-
the expression of human heart chymase is highly com- site effects (773). Transgenic and knock-out studies in
partmentalized and mostly restricted to mast cells (728). mice, however, have not supported this concept in the
Nevertheless, ANG II-generating pathways in the heart heart, since knockout of the AT2 receptor in mice has
that are independent from ACE might be particularly suggested that the receptor is also needed for the media-
important in disease states such as cardiac hypertrophy tion of hypertrophic stimuli (705). Moreover, conflicting
(407) and heart failure (781). experimental data obtained more recently in animal stud-
ies using either selective AT2 antagonists or genetically
4. Angiotensinogen, ANG I, and ANG II modified mice have raised some concern regarding the
beneficial role of AT2 stimulation in both the heart and
The detection of angiotensinogen mRNA in the heart
vasculature in disease states (403).
has been described for mouse (174), rat (268, 417), dog
(382), and human (532). Although the cardiac mRNA lev-
6. Function
els of angiotensinogen are more readily detectable than
those of renin, they are low compared with those found in A) INOTROPIC EFFECTS. Koch-Weser (351) first suggested
liver, the major source of angiotensinogen production that ANG II acts as an inotropic agent (351) but only at
(174). Arguments against local mRNA synthesis of cardiac “supraphysiological” concentrations. The effect could at
angiotensinogen stem from experiments in isolated per- least in part be indirect by ANG II acting, for example, on
fused rat hearts where there was no endogenous angio- the sympathetic nervous system (352). Nevertheless, di-
tensinogen release detectable (144). These authors con- rect effects by ANG II have been verified (148), which are
cluded that the major percentage of cardiac angiotensino- thought to be mediated by intracellular calcium influx and
gen is due to plasma uptake and presented evidence that changes of the plateau phase of the cardiac action poten-
the protein is rapidly taken up into the cardiac interstitial. In vitro studies in human preparations carried out
tium when added to the perfusate. physiological conditions in right atrial and right and left
ANG peptides have been detected in the heart (132, ventricular myocardial preparations of patients with a
416) at concentrations higher than those found in the variety of cardiac diseases suggested that ANG II exerts
plasma compartment. Although this could be seen as an positive inotropic effects only in atrial preparations (286).
indicator of cardiac synthesis, the issue of cardiac uptake However, transgenic overexpression of the human AT1
and local storage of ANG II should be considered. Alter- receptor on cardiac myocytes in a transgenic rat model
natively, renin and angiotensinogen taken up from the has supported the early findings since transgenic AT1
circulation could be interacting with local ACE to lead to upregulation led to an enhanced intracellular calcium
intracardiac ANG II formation. To address this question, response after ANG II stimulation (280).
van Kats et al. (736) used infusions of radiolabeled ANG I B) HYPERTROPHIC EFFECTS. ANG II mediates myocyte hy-
and ANG II peptides in pigs and measured plasma and pertrophy due to activation of the AT1 receptor as an

adaptive response to increased myocardial stress. While with wild-type mice. Cardiac hypertrophy in transgenic
hypertrophy of cardiomyocytes acts initially as a compen- mice is also associated with SERCA2 activity and reduced
satory mechanism to preserve cardiac function, it be- Ca2⫹ transport. Moreover, systolic function was also im-
comes a major risk factor for congestive heart failure and paired as evidenced by impaired contractility in isolated
sudden cardiac death and overall mortality (172). In vitro cardiomyocytes (168). Equivocal results have been ob-
studies have demonstrated this effect in cultured cardio- tained with regard to the role of the AT2 receptor in
myocytes (738), and it has been suggested that this effect cardiac hypertrophy (403). While the AT2 receptor has
is secondary to the release of other growth factors such as been initially associated with antihypertrophic effects
endothelin-1 and transforming growth factor (TGF)-␤ (403), some studies in AT2-deficient mice indicated that
(239). Left ventricular hypertrophy due to enhanced ANG AT2 has a significant effect on cardiac hypertrophy in-
II production in the heart has also been described in duced by aortic banding (635) or ANG II infusion (297).
transgenic rat models with overexpression of RAS com- C) MECHANICAL STRETCH. Several lines of evidence indicate
ponents such as mouse renin (549), the human AT1 recep- that ANG II pathways can be defined as a “rapid response
tor (279, 280), human ACE (555, 711), and double trans- system” for mechanical stretch in the heart, which may be
genic rats expressing human renin and human angio- involved in the mediation of cardiac hypertrophy (100).
tensinogen (470). In some of these models it has been Stretch can induce ANG II release into the media of

clearly shown that the ANG II effects occur independently cultured cardiomyocytes in vitro (587) and in vivo (391),
from its effects on blood pressure, suggesting a functional and virtually the expression of all gene transcripts of the
role of the local cardiac RAS in mediating these changes. RAS can be stimulated by stretch (432). Overload of the
Hypertrophic changes induced by ANG II are mediated by left ventricle, which represents a situation associated
several distinct intracellular pathways such as the activa- with chronic stretch of cardiomyocytes, results in a sim-
tion of tyrosine kinase and RhoA cascades which include ilar activation of the cardiac RAS (29, 626). The intracel-
activation of MAP kinase and JAK/STAT pathways (142, lular pathways activated by the induction of the cardiac
435, 613, 725). An important maladaptation in left ventric- RAS and local ANG II production in cultured neonatal
ular hypertrophy relates to diastolic dysfunction that re- cardiomyocytes are blocked by AT1 receptor antagonism
sults from functional changes such as impaired diastolic (357). The signaling is mediated by p53 as well as by the
calcium handling and/or structural changes such as car- JAK/STAT pathway (391). Whereas initially it was thought
diac fibrosis (101, 586, 629). Studies in rats with experi- that these effects are mediated entirely through the AT1
mental left ventricular hypertrophy indicated that locally receptor, recent AT2 knock-out studies in mice have re-
generated ANG II may disturb relaxation, i.e., diastolic vealed that the AT2 receptor is also involved in mediating
function, of the heart (629). This notion was supported by these changes (635).
subsequent studies in transgenic rats with activated tissue D) REMODELING. Proliferative stimuli by cardiac ANG II
RAS showing significant impairment of diastolic relax- are probably most relevant for the fibroblast portion of
ation (585, 586). Moreover, diastolic function could be cardiac cell population as has been shown by Schelling
restored by treatment with a non-blood pressure-lowering and Ganten (606, 608). Similar mechanisms have been
dose of an AT1 receptor antagonist (586). Functional anal- described during cardiac remodeling where fibroblast
ysis of left ventricular dysfunction in this setting indicated proliferation has been shown as a cellular indicator of
that the impairment of diastolic dysfunction was attribut- pathological changes. Local ACE formation appears to
able to impaired diastolic sarcoplasmic reticulum calcium play an important role in this process, since previous
pump (SERCA2) activity (586). A similar effect could also studies in a rat heart failure model induced by experimen-
be induced in the same rat model by treatment with a tal myocardial infarction (which goes along with in-
selective endothelin A receptor antagonist, demonstrating creased fibrosis) have demonstrated an activation of car-
the activation of the endothelin system in rats with acti- diac ACE activity and mRNA, whereas plasma ACE activ-
vated tissue RAS and its functional consequence in the ity was not changed (277).
heart (585). Chronically, activation of the cardiac RAS In rat hearts, Sun and Weber (687) have shown that at
may not only lead to cardiac hypertrophy and diastolic weeks 1 and 4 after myocardial infarction myofibroblasts
function but also to progressive systolic dysfunction, car- were the predominant cell expressing high-density ANG II
diac enlargement, and heart failure. The independent role receptors at this site, while fibroblasts, macrophages, and
of cardiac RAS activation for these consequences has vessels demonstrated low-density ANG II receptor bind-
been recently demonstrated in transgenic TG1306/1R ing. After myocardial infarction in rats treated with the
mice that develop ANG II-mediated cardiac hypertrophy AT1 antagonist losartan, a significant reduction in colla-
in absence of elevated blood pressure (168). A long-term gen volume fraction at remote sites of the infarction was
follow up study in these mice demonstrated that trans- found compared with untreated animals (139).
genic animals develop dilated cardiomyopathy with aging Since either AT1 blockade or ACE inhibition is not
and exhibit a significant increase in mortality compared associated with any normalization of elevated collagen

mRNA after rat myocardial infarction, Dixon et al. (165) heart surgery, patients with a history of paroxysmal or
suggested that the reduction of cardiac fibrosis mediated persistent atrial fibrillation showed increased interstitial
by ACE inhibition and losartan treatment may reside at fibrosis and threefold higher ACE tissue levels compared
the posttranslational level in cardiac collagen metabo- with patients in sinus rhythm (233), while the densities for
lism. The RAS has apparently multiple targets involved in the AT1 receptor was decreased and increased for AT2
cardiac remodeling. Tan et al. (702) measured the cardio- receptors (231). Most importantly, evidence obtained
toxic effects of ANG II in rats. The authors have shown from recent pharmacological intervention studies has
that pathophysiological levels of endogenous as well as pointed to a new concept in which inhibition of the RAS
nonhypertensive low doses of exogenous ANG II pro- by ACE inhibitors or AT1 antagonists may induce specific
duced multifocal antimyosin labeling of cardiac myocytes benefits in patients with atrial fibrillation (232, 265, 649).
and myocytolysis, increased DNA synthesis rate and fi- E) APOPTOSIS. Whereas earlier studies carried out in
broblast proliferation. Both myocyte injury and fibroblast PC-12 cells (a rat pheochromocytoma cell line) have sug-
proliferation were prevented with captopril (702). gested that programmed cell death is mediated by the AT2
The mechanisms leading to ANG II-induced fibrosis receptor (797), it is generally accepted that apoptosis of
are thought to be at least partially mediated through cardiac myocytes is mediated via the AT1 receptor (99).
growth factor pathways induced by AT1 receptor activa- The process is thought to be involved in cardiac remod-
tion (548, 686). In this context, TGF-␤ has been implicated

eling, for example, after myocardial infarction (19), hy-
as a candidate. Studies on transgenic rats expressing the pertensive cardiomyopathy (163), and diabetic cardiomy-
mouse Ren-2 gene have shown that inhibition of TGF-␤ opathy (206). It can be effectively blocked by AT1 antag-
synthesis by the specific growth factor inhibitor tranilast onists (160), which suggests that the beneficial effects of
did not affect blood pressure but resulted in a significant RAS blockade in heart failure could be due in part to this
alleviation of interstitial cardiac fibrosis seen in this intracardiac mechanism.
model, which was also associated with longer survival of
treated transgenic animals (548).
B. Vasculature
Another mediator, osteopontin, which is involved in
the vascular smooth muscle cell remodeling process, is
The vascular wall is the effector organ for the hor-
increased at mRNA and protein levels after addition of
monal or plasma RAS where AT1 receptors localized on
ANG II to rat cardiac fibroblasts (24, 506). This effect is
vascular smooth muscle cells mediate vasoconstriction.
blocked by the AT1 receptor blocker losartan. This sug-
The concept of a vascular RAS was generated when it
gests that osteopontin is a potentially important mediator
became evident that ANG II can differentially affect
of ANG II regulation of cardiac fibroblast behavior in the
growth properties of vascular cells and that RAS compo-
cardiac remodeling process. Indeed, osteopontin mRNA
nents can be formed intracellularly in the vasculature.
is elevated in transgenic rats, the mouse Ren-2 gene al-
ready in the prehypertensive phase, which suggests that it
1. Renin
contributes directly to the contractile dysfunction seen in
this model and is blood pressure independent (584). Whereas some studies have not found renin activity
Yet another mediator in the inhibition of cardiac in blood vessels (210), others have found renin mRNA
fibroblast proliferation appears to be the recently de- expression in conductance and resistance vessels of hu-
scribed alternative substrate of ACE, AC-SDKP, a hema- man (532) and rat (594). Nevertheless, renin mRNA has
topoetic stem cell regulator, is hydrolyzed by the NH2- been difficult to detect due to the small sample size which
terminal active site of ACE. It has been demonstrated that very often required pooling of samples and the use of
the administration of ACE inhibitors stimulates AC-SDKP more sensitive assays such as RNase protection assays as
plasma levels over fivefold (25), which could be a plasma well as RT-PCR. This has led to a similar controversy as
marker for efficient ACE inhibition. Recently, it has also that concerning renin in the heart, and it has been pro-
been demonstrated that AC-SDKP inhibits also fibroblast posed that local renin synthesis is negligible if at all
proliferation in a dose-dependent manner (554), suggest- present in the vasculature (751). Although this may be
ing that the alternative substrate could be the mediator of true under physiological circumstances, it is possible that
antiproliferative effects on fibroblasts in cardiac remod- local renin production may be turned on in disease states.
eling seen after ACE inhibition. This fascinating hypoth- In this context, vascular renin induction has been dem-
esis, however, awaits final confirmation. onstrated in the rat neointima model (309).
In addition to the structural abnormalities related to In addition to local synthesis, renin uptake via un-
activation of the cardiac RAS, increased activity of the specified binding sites on endothelial cells or specific
system has also been linked to changes in the electrical prorenin/renin receptors (87, 315, 488, 490) has been sug-
physiology that lead to arrhythmias both in the ventricle gested as a relevant mechanism. The M6P receptor was
and atria (146, 266). Indeed, in human patients undergoing shown to bind renin and prorenin on human endothelial

cells (5), and studies in endothelial cells indicated that potential protective effect of ACE2 in lung disease (436,
uptake of prorenin by M6P may represent a clearance 491).
mechanism for prorenin (733). This could in fact provide
a protective mechanism during activation of the RAS 3. Angiotensinogen, ANG I, and ANG II
either systemically or at the tissue level. The potential
The substrate of the RAS cascade has been detected
importance of this mechanisms was shown by generation
in blood vessels at the mRNA level (74, 268). In situ
of a transgenic rat model that directed high prorenin
hybridization studies showed that it is abundantly ex-
expression and release into the plasma from the liver
pressed in periadventitial fat cells (73, 84). This led to the
(740). This led to dramatic increases in plasma prorenin
suggestion that angiotensinogen is secreted by these cells
that were up to 400-fold. Interestingly, these animals did
and diffuses through the vascular wall where it gets in
not have higher blood pressures than controls, yet devel-
contact with vascular renin.
oped severe vascular lesions, suggesting that prorenin is
taken up from the circulation and stimulating the intra-
4. Angiotensin receptors
cellular RAS leading to pathological trophic effects (740).
Moreover, in humans, increases in circulating prorenin Both AT1 and AT2 receptors were identified in the
levels have been associated with disease states such as vasculature (54, 475). Initially the function of these recep-

diabetic microvascular complications (143, 423, 481). It tors was investigated on cultured primary vascular cells.
thus appears of interest for further studies to evaluate the Vascular smooth muscle cells in culture express only the
functional role of prorenin clearance and elimination in AT1 receptor, whereas cultured endothelial cells ex-
the endothelium by M6P or other mechanisms. These pressed both AT1 and AT2 (681). ANG II stimulated
effects have to be balanced against mechanisms such as growth of vascular smooth muscle cells, while the peptide
binding by the prorenin/renin receptor (490) or nonpro- inhibited the growth of quiescent coronary endothelial
teolytic activation of prorenin (296, 689) that would lead cells in response to stimulation by basic fibroblast growth
to the activation of the RAS (87, 315, 488, 490). factor (681). In the presence of an AT2 receptor antago-
nist, this effect was abolished, suggesting a growth-inhib-
2. ACE iting role of AT2 (681). Later, this interesting concept was
also reproduced in an in vivo experiment of AT2 gene
In the vascular wall, ACE is readily detectable, where transfer in balloon-injured rat carotid arteries, which led
it is localized predominantly on the surface of endothelial to a reduction of neointima formation, an effect which
cells (190, 811). There are controversial data regarding the was neutralized by an AT2 antagonist (461). The distribu-
distribution of ACE expression in different layers of vas- tion of the AT2 receptor in the vascular wall is neverthe-
cular wall. Wilson et al. (776) found a predominant label- less a matter of debate (39). Overall, functional studies in
ing in the endothelium and adventitia. This finding was isolated arteries from both animals and humans accumu-
confirmed by Rogerson et al. (578) in human, dog, rabbit, lated a large body of evidence that the endothelium is the
and sheep arteries. Arnal et al. (22) have shown high ACE most important side for AT2 receptor expression (38, 39,
mRNA and protein expression as well as immunoreactiv- 46, 234, 254, 622). In addition, since AT2 may form het-
ity in the media of rat aorta where the expression level is erodimers with AT1 receptors (1), this would require a
almost as high as in the endothelium, while expression is colocalization of both receptors and thus points to the
low in the adventitia. Several reports have indicated that additional expression of AT2 expression on vascular
vascular smooth muscle cells, which do not appear to smooth muscle cells in the vascular wall (39).
express ACE, can do so in certain pathophysiological
situations such as neointima formation (197). Low 5. Function
amounts of ACE have also been detected in the adventitia A) VASCULAR TONE AND ENDOTHELIAL FUNCTION. The tissue RAS
of blood vessels (578). contributes to the maintenance of cardiovascular ho-
ACE2 mRNA expression is ubiquitously found in ar- meostasis by the dual impact on vessel function mediated
terial and venous endothelial cells and arterial smooth through the opposing effects of its two receptors. In in
muscle cells in all organs studied by Hamming et al. (251). vivo studies, i.e., in the whole body situation, it is not
An important role for ACE and ACE2 in the pulmonary possible to clearly dissect between effects mediated by
vasculature and epithelial cells during injury and/or SARS ANG II generated in the plasma and effects attributable to
virus infection has been recently supported (301, 364, ANG II generated within the vessel wall. Nevertheless,
491). However, further studies are required to delineate earlier studies documented the potential of ANG II gen-
the cell types responsible for RAS component expression eration within the vasculature. The local generation of
in the lung and to identify the physiological role of the ANG II in the vasculature has been demonstrated in iso-
pulmonary RAS (436). This will also provide a better lated perfused rat hindquarters (272). Hilgers et al. (272)
understanding of the activated RAS, and particularly the reported that ANG I can be converted to ANG II by ⬃50%

during one pass through a hindlimb. This conversion was dative stress via the AT1 receptor (71, 253, 623). In this
abolished by ACE inhibition. Thus these data supported regard, ANG II plays an important role in modulating the
the presence of a functional vascular RAS in which ACE balance between NO and ROS in the endothelium and
contributed to the local formation of ANG II. In subse- thereby maintaining homeostasis of the vascular wall.
quent experiments it was shown that the vascular produc- Oxidative stress has been shown to play a critical role in
tion of ANG II was endothelium mediated, since the con- the development of endothelial dysfunction and hyperten-
version of ANG I to ANG II was abrogated by endothelium sion and atherosclerosis (4, 253, 623). Nevertheless, the
denudation (273). relative contribution of redox-independent hemodynamic
In response to either systemically or locally gener- mechanisms and oxidative stress in maintaining vascular
ated ANG II, the AT1 receptor mediates the contractile function and their modulation by ANG II via AT1 and AT2
response by phospholipase C-dependent mechanisms receptors needs further in-depth analysis.
leading to an increase in intracellular calcium (142, 604).
It also acts indirectly, by stimulating the synthesis of 6. Tissue remodeling
other vasoconstrictors such as endothelin-1 (535, 582,
614). In contrast, activation of AT2 receptors results in In addition to the well-established long-term effects
activation of protein phosphatases, thereby reversing the of the RAS on vascular remodeling that are mediated by

effects mediated by ANG II binding to AT1 receptors proliferative effects on vascular smooth muscle cells and
(505). Thus the AT2 receptor appears to mediate mecha- fibroblast (9, 75, 223, 227, 607), the production of ROS by
nisms that are counterregulatory and prevent the occur- NAD(P)H oxidase in response to ANG II has been dem-
rence of pathological vascular changes (77, 773). The onstrated as an important mechanism linking activation
functional role of the AT2 receptor was primarily seen of the RAS to events such as inflammation, atherosclero-
during fetal development during which AT2 is highly ex- sis, hypertrophy, remodeling, and angiogenesis (71, 253,
pressed (639, 724). Subsequently, reappearance of AT2 in 623).
the adult organism was associated with pathological The production of ROS by NAD(P)H oxidase in re-
events that can be viewed as fetal-reprogramming. This, sponse to ANG II stimulation in endothelial and vascular
however, does not rule out the possibility that AT2 plays smooth muscle cells activates signal pathways such as
an important role for the regulation of vascular tone and MAP kinases, tyrosine kinases, and transcription factors
blood pressure under physiological conditions (39). In- that lead to theses events (71, 240, 253, 623). In the ANG
deed, a large body of evidence obtained primarily in ani- II/AT1-driven processes leading to vascular damage and
mals supports a role for AT2 receptor-mediated vasodila- chronic atherosclerotic by increased production of ROS
tion (39, 234, 234, 758). Importantly, however, this vaso- by ANG II, additional mechanisms such as low-density
dilatory role of AT2 has been also clearly demonstrated in lipoprotein (LDL) oxidation and uptake, increased LDL-
human coronary microarteries (38, 39), while the effects receptor expression (338, 494), increased expression of
in larger human coronary arteries (38) and human fore- molecular mediators of inflammation such as NF␬B or
arm resistance vessels (429) were not significant (38, 39). cell adhesion molecules such as vascular cell adhesion
Collectively, the vasodilatory effect mediated by AT2 re- molecule (VCAM)-1 or intercellular adhesion molecule
ceptors appears to be predominantly attributable to direct (ICAM)-1 is involved (96, 161, 424, 526). In addition, che-
activation of the nitric oxide (NO)-cGMP pathway, while mokines and proinflammatory cytokines are activated
indirect activation of NO via bradykinin and B2 receptors (96, 424). Moreover, apoptotic changes in response to
as mediators of AT2-induced vasodilation is less well es- ANG II in the vascular wall have been described (162).
tablished (39). However, recent experimental work in This, in addition to ANG II-induced modulation of extra-
hypertensive rats clearly demonstrates that AT2 receptor- cellular matrix components by matrix metalloproteinases
mediated vasodilatation in vivo depends on the blood (MMPs) and tissue inhibitors of MMPs (TIMPs), may play
pressure status (807). In addition to the modulation of a role in vascular remodeling (52, 312) including pro-
vascular tone by ANG II via the NO-cGMP pathway, re- cesses such as the disruption of the normal endothelial
search carried out during the last decade has clearly layer in early atherosclerosis or plaque rupture in more
shown that the effects of ANG II in the vasculature are advanced atherosclerosis (102). Moreover, AT1 and AT2
mediated at least in part by the modification of the redox receptors have been shown to induce opposing effects on
milieu of its target cells (253). ANG II has been shown to vascular smooth muscle cell growth (295). The AT2 recep-
activate the vascular NAD(P)H oxidase(s) resulting in the tor may again be considered as a balancing principle that
production of reactive oxygen species (ROS), namely, counteracts many of the mechanisms indicated above
superoxide and hydrogen peroxide (71, 240, 253, 457, 565, that are mediated by the AT1 receptor. Percutaneous
637, 714). Consequently, ANG II is capable of increasing transluminal coronary angioplasty (PTCA) injury in hu-
NO bioavailability by activation NO-cGMP pathway via mans results in upregulation of ACE at sites of active
AT2 and decreasing NO bioavailability by promoting oxi- repair (509). After balloon injury of rabbit carotid artery

and after pretreatment with perindopril, there was a re- explained by the antiangiogenic actions of ANG-(1O7),
duced neointima formation (316). In contrast, Dale and which can stimulate NO release by interaction with a
Blaine (127) have shown that enalaprilat has no effect on non-type 1 or type 2 ANG receptor (431). Studies in AT2-
neointimal growth or cell proliferation in a vascular organ deficient mice and wild-type mice using the surgically
culture model of rabbit, which may be due to model- induced hindlimb ischemia model indicated that AT2 con-
specific effects. The blockade of the AT1 receptor reduced fers an antiangiogenic effect that is associated with acti-
also neointima growth in a manner similar to that of ACE vation of apoptosis (655). This experiment would ques-
inhibition. The pretreatment with an AT2 receptor antag- tion the beneficial role of AT2 stimulation in the context of
onist, CGP 42112A, did not change the neointima-media pharmacological AT1 blockade in ischemic tissues (403).
ratio (127). The direct involvement of the AT2 receptor in Interestingly, Ac-SDKP, which is inactivated by ACE, has
reducing neointima formation, however, has ultimately been shown to promote neovascularization in the cornea
been shown by direct gene transfer (463). The functional and capillary density in the heart (761).
importance of AT2 has indeed been supported by a study
demonstrating that chronic antagonism of AT2 receptors 8. Gender difference in cardiovascular RAS
led to severe vascular changes such as aortic aneurysms
and arteriosclerosis (136). The vascular changes in AT2 The tissue RAS plays an important role in organs of

knockout mice were less dramatic but pointed in a similar the reproductive system, and components of the RAS are
direction, since animals show elevated blood pressure influenced by gender and sex hormones (207). A large
and an increased sensitivity for DOCA-salt hypertension body of evidence has been obtained through research in
(241). The intracellular mechanisms of these changes animals that components of the RAS are significantly
have been addressed in vascular smooth muscle cells influenced by gender effects at the tissue levels (21, 182,
from AT2 overexpressing transgenic mice (441). The re- 214, 216, 237, 274, 492, 495), while clinical studies in
sults of this study suggest that AT2 activation inhibits JNK humans have predominantly evaluated gender effects on
and c-Jun expression. However, conflicting results have the circulating, i.e., systemic, RAS (98, 129, 235, 261, 262,
also been generated during the last decade, questioning 374, 625, 634). Overall, the role of RAS to explain gender-
the beneficial role of AT2 stimulation in the vasculature, related differences in the cardiovascular system has been
particularly under pathological conditions (403, 404). addressed by many studies in both animals and humans.
Levy et al. (404) demonstrated in normotensive Wistar The characterization of an estrogen-responsive element in
rats receiving hypertensive doses of ANG II that chronic the 5⬘-flanking region of the angiotensinogen gene has
blockade of AT2 with the selective antagonist PD123319 been an important early finding to prove an interaction
had no effect on arterial pressure but antagonized the with sex hormones and the RAS at the molecular level
effect of ANG II on arterial hypertrophy and fibrosis. (192, 237). In addition, angiotensinogen expression in the
Moreover, chronic treatment with a selective AT1 antag- liver is reduced by castration and increased by testoster-
onist lowered blood pressure but still led to smooth mus- one treatment in rats (182). While earlier studies sug-
cle cell hypertrophy and hyperplasia (404). These data gested that renin activity in plasma is stimulated by es-
suggest that the detrimental in vivo effects of ANG II on trogens, more recent studies indicated that renin is actu-
vascular remodeling may be mediated at least in part via ally suppressed by estrogens (207, 508, 625). Castration of
AT2. In this regard, AT2 may contribute to vascular adap- male rats leads to reduction, while testosterone treatment
tation and remodeling by influencing apoptosis in vascu- in ovariectomized female rats increased plasma renin ac-
lar smooth muscle cells (433). However, the effect of AT2 tivity (182). Collectively these studies are in line with the
stimulation on vascular smooth muscle cells may differ observation that renin plasma levels are lower in women
between different cell phenotypes (37) and on the coad- compared with men (207, 625). However, the expression
ministration of AT1 antagonists (706). of ACE mRNA was significantly lowered in response to
estradiol in kidney, lung, and aorta in rats (216). In the
7. Angiogenesis heart, ventricular ACE is more abundant in male than
female mice at both mRNA and protein levels after reach-
Walsh et al. (757) indicated that ANG II can stimulate ing sexual maturity and with increasing age (214). Oopho-
angiogenesis, acting via AT1 receptors within the subcu- rectomy leads only to a slight increase in ACE levels in
taneous sponge granuloma model in the rat and that AT1 female mice, whereas ventricular ACE levels are substan-
and AT2 receptors and ACE develop sequentially during tially decreased in androgen-deprived males (214). Thus
microvascular maturation. This confirms earlier reports the antithetical changes in ventricular ACE abundance
that ANG II stimulates angiogenesis in the chick embryo seen in agonadal male and female mice suggest that tes-
model (387). These authors have also indicated that an tosterone as well as estrogen may play a role in regulating
alternative ANG II receptor is mediating these changes ACE expression in the heart (214). In humans, circulating
(386). It is unclear whether this alternative mechanism is ACE levels appear also to be lower in response to estro-

gens (558, 625, 634). Similarly, AT1 receptor is also down-

regulated by estrogens while estrogen deficiency leads to
upregulation of this receptor (492). In female transgenic
rats with activated tissue RAS, it was shown that estrogen
treatment is protective against hypertension, possibly by
amplifying the vasodilator contributions of ANG-(1O7),
while reducing the formation and vasoconstrictor actions
of ANG II independently of changes from plasma renin
activity (61). In summary, the net effect of estrogens
seems to result in a suppression of the RAS both system-
ically and at the tissue level (207). The role of testoster-
one or androgens has been less well characterized, al-
though more recently Baltatu et al. (32) demonstrated
that treatment with the androgen receptor antagonist flu-
tamide protects against hypertension and end-organ dam-
age not only in male but also in female TGR(mREN2)27

rats.
Despite the evidence that both the activity of the RAS
and cardiovascular morbidity and mortality show gender
differences, it is not fully uncovered to what extent gen-
der and sex hormones regulate the RAS and thereby
mediate effects on the cardiovascular system in men as
well as pre- and postmenopausal women during physio- FIG. 2. RAS in the brain. Two possible ways of ANG II generation
within the CNS are discussed: 1) volume transmission: extracellular
logical conditions (207). Moreover, further study of this generation of angiotensin peptides, acting as neurohormones; and 2)
issue appears of interest for several important issues of wiring transmission: uptake of angiotensinogen by neurons and forma-
clinical medicine such as cardiac and vascular remodeling tion of peptides within the neuron. ANG II acts as neurotransmitter or
cotransmitter (528).
processes in cardiovascular diseases and with ageing as
well as the role of hormone replacement therapy (583). In
this regard, a more recent study is of interest investigating
the variation of the RAS in healthy, premenopausal The existence and functional relevance of the brain RAS
women during predefined phases of the normal menstrual is in the meantime fairly established (31, 592). The con-
cycle (98). In this study it was shown that resting blood cept of local ANG synthesis in the brain is shown in
pressures were lower in the luteal phase of the cycle with Figure 2.
high-estrogen phase (days 15–24) compared with the A) RENIN. Renin activity within the brain was first re-
low-estrogen phase of the cycle despite acute increases of ported by Ganten et al. (220). Although this novel concept
renin and aldosterone during the high-estrogen phase has been challenged by some authors (244), the initial
(98). In addition, in postmenopausal healthy and normo- finding has been confirmed by studies on the subcellular
tensive women it was shown that estrogen replacement localization of brain renin in synaptosomes (530) as well
therapy increases ANG II yet lowers blood pressure, thus as gene expression studies. Renin mRNA was found in the
suggesting that compensatory mechanisms probably at rat and mouse brain (176, 179) albeit at low levels of
the tissue level may protect against the systemic activa- expression (307, 513, 531, 692). Renin activity is present in
tion of the RAS (260). many brain regions of the rat and decreases with the age
of the animals (611). High expression levels of the re-
cently identified prorenin/renin receptor were also de-
C. Nervous System tected in the brain (488, 490). Renin-like activity is high in
hypothalamus and pituitary and pineal glands from rat
1. Central nervous system (270), mouse (666), hog (276), as well as rat and dog (219).
The postulation of an independent brain RAS was Renin protein is measurable in rat primary cultures of
one of the first indications of the presence of local ANG brain cells and neurons, and a strong staining in glia cells
formation in tissues. Bickerton and Buckley (50) had (270) has been observed. Okamura et al. (512) demon-
already shown in 1961 specific central ANG actions using strated renin as well as ANG I and ANG II and ACE in
cross-circulation studies in the dog, and several authors neuroblastoma cells. With the use of double or triple
(202, 635) could demonstrate an interaction between ANG immunogold labeling methods, angiotensinogen, prore-
II and the autonomous nervous system. These data soon nin, and renin were found in lactotrope, gonadotrope,
led to the identification of RAS components in the brain. somatotrope, corticotrope, and thyrotrope glandular cell

types of the rat anterior pituitary (742). The highest levels cortex but also in the superior colliculus, brain stem,
were detected in lactotropes and gonadotropes. amygdala, cerebellum, hippocampus, and olfactory bulb
B) ACE. ACE mRNA is expressed in choroid plexus, of rats (547). In this context, a gender difference between
caudate putamen, cerebellum, brain stem, and hippocam- the level of ANG II in male and female rat brains was
pus of rat brain (772). ACE mRNA was also found in the described. ANG II levels in male rat brains are consis-
pineal gland of rat (33). The localization of ACE protein in tently higher in all tissues except the olfactory bulb. ANG
the brain was verified by quantitative autoradiography II immunoreactivity was found in neurosecretory magno-
(90, 445, 550, 683), with high levels in the choroid plexus, cellular cell groups of the hypothalamus, particularly in
blood vessels, subfornical organ, and organum vasculo- paraventricular nucleus, supraoptic nucleus, as well as
sum of the lamina terminalis, with somewhat lower levels different accessory cell groups using immunocytochemi-
in the thalamus, hypothalamus, basal ganglia, and poste- cal methods (574). This suggests the existence of an
rior pituitary gland. ACE colocalized with renin in synap- intrinsic hypothalamic and a hypothalamo-neurohypoph-
tosomal fractions of these brain structures (530). By au- ysial system, since the fibers from the neurons of the
toradiography the highest concentrations of ACE were accessory nuclei project directly to adjacent blood ves-
found in the choroid plexus, blood vessels, subfornical sels and do not comigrate with the hypothalamo-neuro-
organ, vascular organ of the lamina terminalis, area pos- hypophysial fiber pathway (574).

trema, and inferior olive of the rabbit, and intermediate Schiavone et al. (612) reported that the peptide ANG-
levels of binding were found throughout the basal ganglia, (1O7) is the major metabolite of dog brain stem homog-
midbrain, central gray and the superior colliculus, solitary enates both in the absence and in the presence of angio-
tract nucleus, and dorsal motor nucleus of vagus (579). tensin-converting enzyme inhibitors. These data raised
C) OTHER ANG II FORMING ENZYMES. Possible enzymes in- the possibility of a functional role for ANG-(1O7) in the
volved in brain ANG formation are tonin (615), cathepsin brain. Subsequent studies in the in vitro hypothalamo-
G (349), tissue plasminogen activator, and chymase (34). neurohypophysial system of the rat demonstrated that
Their ultimate functional role in brain ANG formation, ANG-(1O7) is equipotent with ANG II in its activation of
however, remains to be determined. arginine vasopressin (AVP) release (193, 203).
D) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen ANG-(1O7) was found in rat neurons in the supraoptic
mRNA was described in rat brain by Campbell et al. (72) nucleus, and in the anterior, medial, and lateral parvocel-
and Ohkubo et al. (511). Other investigators (427) verified lular, and posterior magnocellular subdivisions of the
these findings using in situ hybridization and localized paraventricular nucleus (363). Three-dimensional recon-
angiotensinogen mRNA in rat cells that stained for glial structions showed that cells immunoreactive to ANG-
fibrillary acid protein, which is a marker for glial cells. (1O7) and vasopressin were specifically codistributed in
Baltatu et al. (33) also found that angiotensinogen mRNA the supraoptic nucleus and in the posterior magnocellular
was colocalized with the astrocyte marker glial fibrillary subdivision of the paraventricular nucleus, suggesting
acidic protein in pineal glands from rats. Angiotensinogen that ANG-(1O7) and vasopressin are colocalized and
mRNA and angiotensinogen immunoreactivity were both coreleased.
present in glial cell populations of all rat cerebellar layers, E) ANGIOTENSIN RECEPTORS. The presence of receptors for
especially in the Purkinje and granular cell layers and ANG has been amply demonstrated in rat brain tissue
within the cerebellar nuclei (419). Astroglia as a main (662, 717–720).
source for angiotensinogen synthesis were also shown by Strong AT1B receptor mRNA expression coincided
other studies (65, 303). In contrast to these findings, some with low AT1A receptor mRNA expression in the anterior
studies have succeeded in demonstrating angiotensino- pituitary of rat, and both receptor mRNAs were detected
gen also in pure neuronal cultures (269). High levels of in the hippocampus, cingulate cortex, and choroid plexus
angiotensinogen and its mRNA are found in hypothala- of rat brain (325). Baltatu et al. (33) have detected that in
mus and brain stem (268, 427, 572). In dog brain, ⬃95% of rat pineal gland AT1B mRNA expression exceeded the
recovered angiotensinogen has been reported to be extra- expression AT1A mRNA and was colocalized with the
cellular (466), and Thomas et al. (709) have demonstrated pinealocyte-specific tryptophan hydroxylase. AT1A recep-
the distribution of angiotensinogen in the rat brain by tor mRNA but not AT1B or AT2 mRNA as expressed in the
immunocytochemistry. This is supported by findings that subfornical organ and paraventricular nucleus of the rat
the cerebrospinal fluid of dog and rat contains consider- hypothalamus, and AT1B as well as AT1A mRNA were
able amounts of angiotensinogen (455, 609). found in the cerebral cortex and hippocampus of rat;
The impermeability of the blood-brain barrier and conversely, AT2 mRNA, but not AT1A or AT1B, was ex-
blood-cerebrospinal fluid barrier for ANG II was reported pressed in the medial geniculate nucleus and inferior
by several authors (329, 610, 747). With the use of radio- olive of rat (324).
immunoassay and HPLC analysis, ANG II was found with AT2 mRNA was found in several thalamic nuclei,
the highest levels in the hypothalamus, pituitary, and medial geniculate nuclei, the nucleus of the optic tract,

the subthalamic nucleus, the interposed nucleus of the was reported that astrocytes of rats express AT1 recep-
cerebellum, and the inferior olive of rat (323). tors. AT2 receptors were detected immunohistochemi-
Expression of AT1B receptor mRNA was present in cally within the hypothalamic paraventricular and the
33% of rat anterior pituitary cells, predominantly ex- supraoptic nuclei of the rat brain, and more specifically, in
pressed by lactotropes and to a lower degree by cortico- neurons also containing vasopressin (642). But in those
tropes and is not detectable in somatotropes, mammo- structures there is a lack of AT2 binding using receptor
somatotropes, gonadotropes, or thyrotropes (385), in con- autoradiography, suggesting that AT2 receptors are trans-
trast to the distribution of angiotensinogen, prorenin, and ported to the posterior pituitary.
renin in the anterior pituitary. Using a gene targeting approach in mice, Davisson et
High ANG II binding sites were found in medulla, al. (137) have proposed that the AT1A receptor is mainly
hypothalamus, and circumventricular organs of rat (222). involved in central blood pressure control while the AT1B
Moderate to strong AT1A labeling was found in the ante- receptor is responsible for mediating the drinking
rior olfactory nucleus, the piriform cortex, and the nu- response.
cleus of the lateral olfactory tract (384). With the use of AT4 receptors as ligands for ANG IV are located in
immunohistochemistry, the AT2 receptor was detected in brain areas implicated in memory acquisition and re-
the locus ceruleus, bed nucleus of the accessory olfactory trieval, stress, and spatial learning (785). Specific ANG IV,

tract, and cerebellum in association with the Purkinje cell ANG-(3O8), binding sites were found in the forebrain, in
layer, and the deep cerebellar nuclei of the rat brain particular in the cortex, the hippocampus, the amygdala,
further structures were hippocampus, limbic structures, the thalamus, and the hypothalamus of mice (749). Rat
thalamic areas, and hypothalamic areas (570). In the AT4 receptors were found in cerebral cortex, piriform
mouse brain AT1 and AT2 receptor distribution was sim- cortex, hippocampus, habenulae, colliculi, septum, peri-
ilar to that of the rat, with some notable exceptions, such aqueductal gray, several thalamic nuclei, the arcuate nu-
as the presence of AT1 but not AT2 receptors in the locus cleus of the hypothalamus, and cerebellum (575). The
cerulus and the expression of AT1 receptors in the cau- authors have shown that after intracerebroventricular
date putamen (264). MacGregor et al. (430) have shown (ICV) injection of ANG IV, Fos-like immunoreactivity was
that the ANG II binding sites in all forebrain, midbrain, present in the hippocampus and piriform cortex and that
pontine, medullary, and spinal cord sites, as in the small this effect is only blocked by a specific AT4 receptor
and large arteries in the adjacent meninges and choroid antagonist. In sheep spinal cord, a high density of ANG IV
plexus of the human was of the AT1 subtype. And both binding sites was localized to the perikaryon and pro-
AT1 and AT2 receptors occur, in contrast to the rat, in the cesses of all somatic motor neurons, the autonomic motor
molecular layer of the cerebellum. AT1 immunoreactivity neurons in the lateral horns of thoracic and lumbar seg-
was detected in several hypothalamic nuclei, substantia ments and all dorsal root ganglia and also in numerous
nigra, locus ceruleus, nucleus tractus solitarius, ventrolat- motor-associated regions at the supraspinal level, with
eral medulla, pontine nuclei, and inferior olivary nucleus weaker binding observed in the sensory regions (452). In
of the human brain (44). Brain ANG II receptors are macaca fascicularis brain, AT4 receptor binding sites
differentially regulated by a number of stimuli. Chemical were found in motor nuclei and motor-associated regions
lesions of the young rat inferior olive reduced ANG II as ventral horn spinal motor neurons, all cranial motor
binding to AT2 receptors and AT2 receptor mRNA levels in nuclei including the oculomotor, abducens, facial and
this area by 50% and produced a similar decrease in AT2 hypoglossal nuclei, and the dorsal motor nucleus of the
receptor binding in the molecular layer of the cerebellar vagus, in the vestibular, reticular and inferior olivary nu-
cortex (322). The extent of binding reduction was similar clei, the granular layer of the cerebellum, and the Betz
3 and 7 days after the lesion. Interestingly, the authors cells of the motor cortex with moderate receptor density
have detected only AT2 binding sites in the molecular in all cerebellar nuclei, ventral thalamic nuclei, and the
layer and not AT2 receptor mRNA. The lesions did not substantia nigra pars compacta; abundant AT4 receptors
change ANG II binding to AT1 receptors in the molecular are also found in the areas associated with cholinergic
layer or AT1 receptor mRNA levels in Purkinje cells; also nuclei and their projections, including the nucleus basalis
AT2 receptor binding and AT2 receptor mRNA levels in of Meynert, ventral limb of the diagonal band and the
the deep cerebellar nuclei were not affected according to hippocampus, somati motor nuclei, and autonomic
the authors. A weak, diffuse cytoplasmatic AT1 receptor- preganglionic motor nuclei (454).
like immunoreactivity was observed in almost all the There is still the possibility that we have not yet
catecholaminergic cell bodies of the A2, C1, C2, and C3 discovered all relevant ANG II receptors. In the gerbil
cell groups of rat, except those of the A1 cell group (801). brain and pituitary, most of the ANG II receptors are
In addition, the AT1 receptor-like immunoreactivity was different from AT1, AT2, and AT4 subtypes (149).
seen in noncatecholaminergic neurons. With the use of The Mas protooncogene, a heptahelical receptor in
electrophysiological (287) and autoradiographic studies it search of a specific ligand, has been proposed as a medi-

ator of ANG II-related effects in the brain (15, 311). While affect the central sensitivity of the cardiac sympathetic
it appears unlikely that Mas is a specific receptor for ANG afferent reflex or the baseline hemodynamics, but the
II, it has been suggested as an enhancer of AT1-mediated baseline of renal sympathetic nerve activity increased
effects in the brain (750). Aside from this functional in- during the infusion of ANG II (428). However, chronic ICV
teraction, Mas could also act as a specific receptor for infusion of ANG II enhanced the central sensitivity of the
alternative ANG peptides such as ANG-(1O7), which cardiac sympathetic afferent reflex via AT1 receptor. In
should be verified. Knock-out studies of Mas showed that addition, chronic ICV infusion of ANG II elicited an in-
it plays an important role as a modulating factor in the crease in arterial pressure. In mice, the blood pressure
electrophysiology of the hippocampus (759). increase elicited by centrally administered ANG II is most
F) FUNCTION. I) Blood pressure regulation. The brain likely due to AT1A receptor activation (137). However, the
RAS appears to play a prominent role in central blood drinking response requires the presence of AT1B
pressure regulation. There is increased activity of renin in receptors.
several nuclei of the brain stem and in neurohypophysis Increased AT1 expression in the brain has been sug-
of young hypertensive rats when compared with age- gested as an early marker for the development of hyper-
matched normotensive control animals (611). The higher tension. AT1 protein levels were higher in the brain stem
renin mRNA concentration in the brain stem of SHR of the Zucker obese rat (53), a rat model with a predis-

appears to be at least partially determined by the geno- position for hypertension. An ICV injection of ANG II in
type of the renin gene (648). The binding activity of AGE these rats caused a significantly greater increase in blood
2 (angiotensinogen gene activating element) and angio- pressure compared with control animals. Similar changes
tensinogen mRNA levels were higher in the brain of spon- are seen in other cardiovascular disorders. Higher binding
taneously hypertensive rats (SHR) compared with con- densities for AT1 receptor were found in the subfornical
trols (500). In hypertensive rats (SHR) there were also a organ, paraventricular hypothalamic nuclei, and solitary
significantly higher numbers of measurable AT1 and AT2 tract nuclei in rats with chronic heart failure compared
receptor subtypes in the hypothalamus compared with with controls (803). Thus, in rats with chronic heart fail-
controls (252). This is not a secondary phenomenon, since ure, AT1 expression is increased in brain regions that are
transgenic approaches leading to a permanent reduction closely related to water intake, vasopressin release, and
of angiotensinogen in the brain show opposite character- hemodynamic regulation.
istics. Basal systolic blood pressure was significantly In rat hypothalamus there is an inhibitory effect on
lower in transgenic rats with permanent inhibition of noradrenergic neurotransmission caused by ANG-(1O7)
brain angiotensinogen synthesis compared with controls which has been suggested to be mediated by the AT2
(35, 616). Mice lacking the AT2 receptor gene have an receptor (229). Furthermore, inhibition of NO synthase
increase in blood pressure and increased sensitivity to (NOS) prevented this effect, suggesting the involvement
pressure effects of ANG II (298). Chronic subcutaneous of NOS-related mechanisms. Rats pretreated with NG-
administration of CV-11974, an AT1 receptor antagonist, nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor,
shifted the brain autoregulation curve toward lower blood showed a greater pressure response to ANG II microin-
pressures in rats and markedly decreased the expression jection into the rostral ventrolateral medulla, than in rats
of AT1 receptors both in areas outside the blood-brain without L-NAME treatment (716). Microinjection of the
barrier (subfornical organ, 95% decrease) and inside the AT1 receptor antagonist CV11974 into the depressor re-
blood-brain barrier (nucleus tractus solitarius, 87% de- gion within the nucleus tractus solitarii of rat produced
crease, and paraventricular nucleus, 96% decrease) (503). greater decreases in arterial pressure, heart rate, and
It has been reported that ANG II can increase blood renal sympathetic nerve activity in L-NAME-treated rats
pressure when administered directly into the brain (50). than in control rats (188). In addition, ACE mRNA levels
This action could be partially due to an interaction with in the brain stem were greater in L-NAME-treated rats
the sympathetic nervous system. Bilateral microinjection (188).
of ANG II and ANG III into the nucleus tractus solitarii The brain RAS is closely linked to central vasopressin
significantly and dose-dependently suppressed the actions. The transgenic rats with reduced (⫺90%) brain
baroreceptor reflex of rats (426). The suppressive effect angiotensinogen levels described above exhibit a diabetes
of ANG II was reversed by coadministration of the AT1 insipidus-like syndrome producing an increased amount
receptor antagonist losartan. of urine with decreased osmolarity (616). There was also
The intraventricular infusion of ANG II in conscious a reduction in plasma vasopressin by 35% in these ani-
normotensive rabbits decreased cardiac baroreflex gain mals. Kagiyama et al. (330) suggested that the reduction
by 20 –37%, whereas losartan infusion increased barore- of angiotensinogen in rats plays important roles in vaso-
flex gain by 24 –58%; blood pressure and heart rate were pressin release and sympathetic nerve activity but may
not altered by any treatment (221). Acute infusion of ANG not contribute to the maintenance of arterial pressure in
II into dog cerebroventricular region of the brain did not hypertensive rats. ICV administration of ANG II and ANG

III in rats significantly increased renal plasma flow, glo- In cattle, ICV infusion of losartan induced a dose-
merular filtration rate, urine flow, absolute and fractional dependent inhibition of the high water intake caused by
excretions of sodium and potassium, and decreased renal water restriction or by ANG II infusion but did not affect
efferent nerve activity; in higher levels, it also increased salt appetite (51). Treatment with saralasin, a nonselec-
blood pressure (94). ANG II produced antidiuretic effects tive ANG II receptor antagonist, into the median preoptic
in a dose-dependent manner when microinjected into the nucleus area of rats produced significantly attenuated
supraoptic and paraventricular nuclei of rats (593). This saline intake, but had no effect on water intake (703). In
effect is reduced by pretreatment with a vasopressin addition, the direct injection of ANG I into the rat subfor-
antagonist. nical organ stimulated drinking, which was blocked by
Pharmacological inhibition of the brain RAS has ben- losartan pretreatment (791). Prior administration of losar-
eficial effects in the brain. Intracerebroventricular infu- tan into rat supraoptic nucleus decreased water and so-
sion of captopril significantly attenuates the pressor re- dium intake induced by the injection of ANG II into the
sponse produced by systemically infused ANG I (576). medial septal area of water-deprived rats (18). This effect
Losartan injection into the anterior hypothalamic preop- was not seen by administration of PD123319, an AT2
tic area produced a depressor response in SHR and receptor antagonist, applied directly into the supraoptic
DOCA-salt hypertensive rats but not in normotensive nucleus. AT2 receptor stimulation inhibits drinking re-

Wistar-Kyoto rats, whereas ANG II injection into the same sponse and vasopressin release following centrally ad-
area produced a pressor response in sham-operated, ministered ANG II in rats (283).
Wistar-Kyoto rats, SHR and DOCA-salt hypertensive rats, Dehydration differentially upregulates angiotensino-
and the pressor response to ANG II was greater in DOCA- gen and AT1A receptor mRNA formation in distinct re-
salt hypertensive rats and SHR than that in sham-operated gions of the rat subfornical organ (36). ICV administration
rats and Wistar-Kyoto rats (365). There was also a greater of losartan completely blocked water intake caused by
release of ANG peptides in the anterior hypothalamic ICV administration of ANG II, and following food depri-
preoptic area of DOCA-salt hypertensive rats as in the vation, food intake was reduced by PD123319. Interest-
anterior hypothalamic preoptic area of sham-operated ingly, neither water intake after water deprivation nor
rats. The ACE inhibitor imidapril reduced edema forma- sodium intake after sodium depletion were altered by
tion in the cortex, hippocampus, and striatum of rats losartan or PD123319 (768). ANG II microinjected into the
suffering from stroke (792), and the progression of neu- organum vasculosum prelamina terminalis increased wa-
rological deficits with loss of learning ability was sup- ter consumption but did not induce intake of a hypertonic
pressed. Treatment of stroke-prone SHR rats with perin- NaCl solution. Again this effect was antagonized by losar-
dropil prevents stroke through the suppression of blood tan (181). The dose-response curve for water intake after
pressure elevation and prevention of tissue damage in the ICV injections showed a higher sensitivity to ANG II in
brain (762). Nishmura et al. (502) have shown that pre- transgenic rats with specific downregulation of astroglial
treatment with the AT1 antagonist candesartan protected synthesis of angiotensinogen compared with controls
hypertensive rats from brain ischemia by normalizing the (458).
cerebral blood flow response, most likely through AT1 Water deprivation upregulates AT1 binding and
receptor blockade in cerebral vessels and in brain areas mRNA in rat subfornical organ and anterior pituitary
controlling cerebrovascular flow during stroke. (598). Following direct stimulation of the rat paraven-
II) Drinking and food intake. Epstein et al. (185) tricular nucleus with hyperosmotic solutions, concentra-
discovered that ANG II elicited drinking when centrally tion-dependent increases in ANG II immunoreactivity
administered into the brain of the rats. ICV administration were found (561). The centrally induced natriuresis and
of renin to rats also induced vigorous drinking behavior blood pressure response to hypertonic saline that is ICV
(790). These effects are reduced when renin-injected rats administered involves AT1 receptors in the subfornical
were pretreated with captopril. Other studies showed that organ of rats (580).
the ICV infusion of captopril completely blocked the III) Function of the blood-brain barrier. The local
drinking response produced by systemically infused ANG RAS in the brain is thought to play a functional role in the
I (576). Conversely, a high sodium intake increased the maintenance of the blood-brain barrier. Angiotensinogen
renin mRNA in the rat hypothalamus, despite the lowering but not renin levels in the brain appear to be relevant for
in renal renin mRNA (501) showing the independent reg- this function, since a decrease in density in granular layer
ulation of the brain RAS by this stimulus. Chronic ICV cells of hippocampus and an impaired blood-brain barrier
infusion of ANG II into the dog elicited an increase in function which is seen in angiotensinogen-deficient mice,
water intake (428). ICV infusion of losartan reduced post- whereas renin-deficient mice do not show this phenotype
prandial drinking in sheep but did not affect food intake, (799). Other studies in knock-out mice came to similar
while the intravenous administration had no effect on conclusions. Astrocytes of angiotensinogen knockout
drinking (440). mice had very attenuated expression of glial fibrially

acidic protein and decreased laminin production in re- and paraventricular nucleus, whereas c-Jun expression
sponse to cold injury, and ultimately incomplete reconsti- was restricted to the median preoptic area, subfornical
tution of impaired blood-brain barrier function (331). organ, and paraventricular nucleus, and JunB was only
These data are in contrast to reports by Rose et al. induced in the median preoptic area and subfornical or-
(581) who suggested AT1 receptor-mediated uptake and gan. Losartan prevented the ANG II-induced immediate
transport of ANG II at the site of the bovine blood-brain early gene protein expression. Also the direct injection of
barrier. This has been questioned since there is no evi- ANG I into the rat subfornical organ induced Fos immu-
dence that angiotensins cross the blood-brain barrier and noreactivity in the anterior third ventricle and in the
penetrate noncircumventricular organ structures (256). vasopressin neurons of the supraoptic and paraventricu-
Monti et al. (458) found functional upregulation of lar nuclei, which was blocked by losartan pretreatment
the AT1 receptors inside the blood-brain barrier in a trans- (791). ANG II produced an upregulation of the AT2 mRNA
genic rat line with specific downregulation of astroglial level in rat cortical neurons (645). This was blocked by an
synthesis of angiotensinogen. The authors have found a AT2 receptor antagonist. It has also been shown that
higher AT1 receptor binding in most of the regions inside growth hormone upregulates AT1A receptor in primary
the blood-brain barrier in transgenic rats compared with cultures of rat astrocytes by a transcriptional mechanism
controls. In contrast, in the circumventricular organs in- (788). AT2 stimulation promotes differentiation and ax-

vestigated, AT1 receptor binding was significantly lower onal regeneration and inhibits proliferation of neuronal
in transgenic rats. cells (421, 443, 674). ANG II induces increased elongation
IV) Central actions on the reproductive system. In of neurites and cell migration in microexplant cultures of
the pituitary of female rats, mRNA levels for angiotensino- the cerebellum from 3-day-old rats via activation of AT2
gen were increased by 45% following estrogen adminis- receptors (112). Furthermore, the authors have shown an
tration (346). These authors also demonstrated that estra- increase in expression of neurite-specific ␤-III-tubulin and
diol caused a 30 – 40% reduction in the levels of AT1 mRNA microtubule-associated proteins tau and MAP2 and that
in pituitary and hypothalamic-thalamic areas of the fe- AT1 receptor inhibits the AT2 effect. In another study the
male rat. A reduction in ANG II binding to AT1 receptors same authors (113) were able to demonstrate that ANG II,
in the pituitary and the subfornical organ was measured via the AT2 receptor, induces nitrite formation from NO
following estrogen treatment. AT1A receptor mRNA ex- which was abolished by L-NAME. Furthermore, the treat-
pression is induced by estrogen-progesterone in dopami- ment of the neuronal cell culture with SNAP, an exoge-
nergic neurons of the female rat arcuate nucleus (326). nous source of NO, induced the same morphological dif-
ANG II immunoreactivity into rat cerebrospinal fluid was ferentiation. Other mechanisms that could be responsible
greater on proestrus compared with diestrus day 1, and in for AT2-related effects include stimulation of the serine/
the overall comparison of ANG II immunoreactivity was threonine phosphatase A2 and inhibition of MAP kinases
released from the preoptic-anterior hypothalamic area, Erk1 and Erk2 (292). AT2 receptor upregulation may be
significantly more ANG II immunoreactivity was released involved in apoptosis and tissue repair after stroke, since
on the day of proestrus versus diestrus day 1. ANG II AT2 receptor gene expression was found to increase in
increased prolactin release and produced an immediate the infarct cortex of rats with permanent occlusion of the
spike of intracellular Ca2⫹ followed by a plateau in cells middle cerebral artery (810). Additional data emerged
from rat pituitary (158). These effects were blocked by that lend further support to the idea of the involvement of
losartan but not by PD123319, confirming the functional local RAS in tissue death after stroke. A recent study
link of the system. reported a decrease in infarct volume and cerebral edema
V) Induction of transcription and translation. Cen- of rats after reperfusion injury when animals, without
tral RAS stimulation induces a program of transcription affecting systemic hemodynamics, were treated with an
factors commonly associated with the regulation of neu- ACE inhibitor (289).
roplasticity. ICV administration of renin to rats induced Neurons cultured from newborn rat hypothalamus
Fos and Egr-1 immunoreactivity in the subfornical organ; and brain stem undergo apoptosis when exposed to ultra-
median preoptic, supraoptic, and paraventricular nuclei; violet (UV) radiation. This effect is enhanced by ANG II
area postrema, nuclei of the solitary tract; and lateral and can be blocked by the AT2 receptor antagonist
parabrachial nuclei (790). PD123319 (644). Additionally, ANG II enhanced the UV
Similar findings have been described by Lebrun et al. radiation-induced decrease in the levels of the DNA repair
(378), who after ICV ANG II infusion in rat brain found a enzyme poly-(ADP-ribose) polymerase. The MAP kinases
dose-dependent expression of c-Fos and Krox-24 in the in the rat brain neuronal cultures are activated by AT1
subfornical organ, the median preoptic area, and the para- receptors and inhibited by AT2 receptors, again pointing
ventricular nucleus and supraoptic nucleus of the hypo- to dual functions of these receptors (292).
thalamus. Furthermore, FosB expression was induced VI) Temperature regulation. AT2-deficient mice ex-
after ICV injection of ANG II in the median preoptic area hibited a lower body temperature compared with controls

and show smaller hyperthermia after intraperitoneal in- neously observed decreased in brain 5-HT levels, suggest-
jection of interleukin-␤ and greater increase in body tem- ing a cross-link to the serotonergic system (746).
perature and physical activity after nonimmunological Sakagawa et al. (591) have shown that the pain threshold
stress (766), suggesting a role for the brain RAS in tem- was significantly lower in AT2-deficient mice, compared
perature regulation. with findings in wild-type mice, and that the fluorescence
VII) Motor control. Either bilateral or unilateral mi- intensity of ␤-endorphin in the arcuate nucleus of the
croinjections of ANG II into the hippocampal CA1 area of medial basal hypothalamus was significantly lower in AT2-
rats affected locomotor activity in a dose-related deficient mice, compared with findings in wild-type mice.
U-shaped manner (41, 42). The effect was more pro- Furthermore, the authors found that the AT2 receptor
nounced when ANG II was microinjected into the left CA1 does not influence learning behavior and brain edema
area. formation.
VIII) Visual system. Microinjection of ANG II in the Dexamethasone injection in rats caused an increase
superficial layers of the superior colliculus of rat yielded in AT1 receptor mRNA in the hypothalamic paraventricu-
a strong reduction in the amplitude of visual evoked lar nucleus, and AT1 mRNA is also increased after expo-
potentials in a dose-related manner (114). Merabet et al. sure to stress paradigms associated with activation of the
(446) have shown that in rat this is predominantly medi- hypothalamic-pituitary adrenal axis (6).

ated by AT1 receptor (446).
IX) Behavior and emotions. Belcheva et al. (43) 2. Peripheral nervous system
suggested that ANG II facilitates learning and memory of
rats, especially when microinjected into the left CA1 hip- A) SYMPATHETIC NERVOUS SYSTEM. ANG II binding sites were
pocampal area. Winnicka (777) has detected that bilateral localized and quantified in rat stellate and superior cervi-
6-OHDA lesions to rat central amygdala (CA) totally abol- cal ganglia by quantitative autoradiography (85). High
ished the facilitatory effect of ICV infusion of ANG II on densities of AT1 receptors in sheep (516) and ANG II
the retrieval process in a passive avoidance situation immunoreactive terminals in guinea pig and rat (215, 414)
(777). ANG II significantly increased the amplitude of field occur in the intermediolateral cell column of the spinal
potentials, of the rat lateral nucleus of the basolateral cord and the central autonomic area.
amygdala, induced by the electrical stimulation, whereas A direct relationship between the effect of ANG II
ANG IV caused a significant decrease in the amplitude of and the sympathetic nervous system is likely since sym-
field potentials (748). Wright et al. (786) suggested that pathectomy or reserpine treatment attenuates the blood
the brain ANG IV-AT4 system plays a role in the formation pressure response to ANG II. Intrathecal administration
of spatial search strategies and memories, since the AT4 of ANG II increases sympathetic vasomotor nerve dis-
receptor is heavily distributed in the CA1-CA3 regions of charge and blood pressure in rats (688). The interaction of
the hippocampus, and chronic ICV administration of AT4 ANG II with postganglionic nerve terminals was shown by
agonist (Norleucine1-ANG IV) facilitated the rate of ac- Day and Owen (138). In addition, Lewis and Reit (406)
quisition to solve the spatial learning task. ANG II and have shown that ANG II potentiates sympathetic trans-
ANG-(3O7) improved object recognition in sham-oper- mission through the sympathetic ganglia of the cat.
ated rats to nucleus accumbens septi and to nucleus septi ANG II is able to increase the excitability of superior
lateralis, and bilateral 6-OHDA lesions to nucleus accum- cervical ganglia cells (640) and cells from sympathetic
bens septi totally abolished and to nucleus septi lateralis region of the thoracic and lumbar spinal cord or rat (405).
attenuated the facilitatory effect of both ANG peptides on Cox et al. (117) have shown that ANG II and ANG III were
object recognition (778). This suggests that dopaminergic able to facilitate the action potential-induced release of
projection to the septum mediale mediates facilitatory norepinephrine via a prejunctional AT1 receptor in mouse
effect of angiotensins on recognition memory in rats atria and spleen. In the rat, ANG II caused an increased
(778). sodium and water absorption that is mediated by in-
Mice lacking angiotensinogen displayed the reduc- creased norepinephrine release from sympathetic neu-
tion of “depressive-like” behavior in the behavioral de- rons (400).
spair swim test and spontaneous locomotor activity di- Upregulation of ANG II release and angiotensinogen
minished; however, they showed no axiogenic-like or mRNA expression can be induced by high-frequency
memory-deficit behavior, and there was no change in the preganglionic stimulation at the canine cardiac sympa-
pain threshold (515). This was confirmed in other studies thetic ganglia (369). The resulting positive chronotropic
where mice lacking angiotensinogen show no differences responses were inhibited by the nonpeptide AT1 receptor
compared with controls in anxiety and learning (760). antagonist forasartan or the ACE inhibitor captopril,
However, transgenic rats with diminished angiotensino- while the increase in heart rate elicited by postganglionic
gen production showed more signs of anxiety than con- stellate stimulation could not be inhibited by these com-
trol animals. An effect most likely due to the simulta- pounds (369).

B) PARASYMPATHETIC NERVOUS SYSTEM. In vitro autoradio-

graphic techniques demonstrate a high density of AT1
receptors in intracardiac ganglia and conduction systems
of rat heart (14, 590), but it is not known if they are
localized presynaptically or postsynaptically. Allen and
co-workers (11, 12) detected that ANG II receptors are
transported peripherally in the rat vagus nerve and may
well be localized on the terminals of parasympathetic
preganglionic neurons whose cell bodies lie in either the
nucleus ambiguus or dorsal motor nucleus of vagus in the
medulla. Diz and Ferrario (166) provided data that reveal
the existence of a mechanism for the bidirectional axonal
transport of ANG II binding sites in the cervical portion of
the vagus nerve of dogs.
Potter (556) has shown that ANG II inhibits release of
acetylcholine from the preganglionic neurons via a pre-

synaptic mechanism in intact dogs and in isolated guinea
pig atria.
Ikegami et al. (300) showed that ⬃70% of hamster
submandibular ganglion neurons responded to ANG II
with persistent depolarization. This effect is mediated by
AT1 receptor subtypes. The AT2 receptor has been implied
in neurotropic effects in the peripheral nervous system,
since it could be demonstrated that AT2 effects promote
axonal regeneration after optic nerve crush in a tissue
FIG. 3. RAS in the ovary. Renin, synthesized and secreted by theca
culture model (421). cells, leads to local ANG production. Two possible ways in which ANG
C) SENSORY NEURONS. There are suggestions that AT1 re- II may modulate atresia in ovaries has been suggested: 1) ANG II is
ceptors are associated with a range of afferents nerves. acting on the AT2 receptor within the same follicle by an autocrine
mechanism leading to apoptosis and atresia; and 2) ANG II is secreted
AT1 receptors were detected on cell bodies in nodose by preovulatory follicles causing apoptosis in adjacent atretic follicles
ganglion, dorsal root ganglia, and the primary central (paracrine mechanism). Follicular fluid contains high levels of renin and
terminal regions of these neurons, the nucleus of the ANG II.
solitary tract and dorsal laminae of the spinal cord of
several species (10, 11, 516). It has also been suggested I) Renin. Ovarian renin mRNA was detected by sev-
that AT1 receptors occur in the caudal nucleus of the eral authors (304, 341, 411). Renin mRNA is expressed in
spinal trigeminal tract in the medulla (13) and that they the corpora lutea of the rat but not in theca or granulosa
may be associated with the terminals of trigeminal sen- of follicles. Follicle-stimulating hormone stimulates renin
sory neurons. mRNA expression in the ovary of rat (342) and monkey
(304).
The ovary is the major source of plasma prorenin in
D. Reproductive Tract
women (230). The rat ovary contains a moderate amount
of prorenin and renin activity, which are increased by
1. Female reproductive tract
pregnant mare serum gonadotrophin (497). Renin is dif-
As reviewed by Hagemann et al. (249), renin has been ferentially expressed across species borders. Bovine cor-
detected in the uteroplacental unit of many species. Skin- pora lutea express high levels of renin activity, while
ner et al. (660) showed that all parts of the human utero- porcine corpora lutea have very low levels of renin activ-
placental unit contain renin, with the highest concentra- ity (496). In the cow, ovarian follicles contain prorenin
tions found in the fetal membranes (chorion and amnion) and renin, with the highest level of prorenin expression in
and decidua. In humans, prorenin is the major form of atretic follicles (469, 624). Lightman et al. (411) detected
renin in the uteroplacental unit (332, 765). Secretion of renin mRNA in the gonadotropin-stimulated rat corpus
prorenin from the human uteroplacental unit (57, 388) luteum using in situ hybridization histochemistry. No pos-
and the corpus luteum (151) may explain the increased itive signal was detected in theca or granulosa cells.
plasma prorenin concentrations in pregnant women, Howard et al. (290) suggested that renin activity, which
which is more pronounced in the first trimester (632). varies with the estrous cycle, arises from theca or inter-
A) OVARY. A schematic representation of the localiza- stitial cells of the rat ovary. As mentioned above, Itskovitz
tion of RAS components in the ovary is shown in Figure 3. et al. (304) could detect renin mRNA in the theca of

human chorionic gonadotropin (hCG) stimulated monkey and on the epithelial cells of the fallopian tubes of the
ovaries but not renin-like immunoreactivity, suggesting nonpregnant sheep. ACE immunoreactivity showed a cy-
that the product is immediately secreted. Unlike this find- clic variation in the human endometrium with the highest
ing in the human, renin-like immunoreactivity has been expression in the late secretory phase at the menses
observed in theca, stromal, luteal, and granulosa cells (410).
(518, 519). Renin-like activity has also been found in Furthermore, the uterus contains cathepsin D (599)
human follicular fluid (412). and chymase (731), giving rise to possibilities for alterna-
II) ACE. ACE is abundant in the rat ovary (126). Rat tive pathways for ANG II formation in the uterus.
ovarian ACE is membrane bound and is present in the III) Angiotensinogen, ANG I, and ANG II. Angio-
germinal epithelium, capsule of the corpora lutea and in tensinogen mRNA is expressed in spiral artery smooth
many, but not all, follicles (669). In the human ovary, ACE muscle in human uterine deciduas (459), but the stroma
activity increases with age (187), which could be a result of the uterus itself does not appear to produce angio-
of the age-dependent reduction in the number of ovulat- tensinogen (218, 299). Immunoreactive ANG II was found
ing follicles rather than a direct regulatory effect. by Naruse et al. (479) in human uterus. Rat uterus also
III) Angiotensinogen, ANG I, and ANG II. Angio- contains immunoreactive ANG II (154). ANG II-like im-
tensinogen mRNA has been shown to be expressed in the munoreactivity was detected in human proliferative en-

ovary of rat and mouse (511, 701). By immunocytochem- dometrium (glandular epithelium and stroma) with cyclic
istry, Thomas and Sernia (710) have found angiotensino- changes (8). In the proliferative phase, ANG II immuno-
gen activity in specific populations of granulosa cells of reactivity was expressed in the glandular epithelium and
the rat ovary and, to a lesser extent, in germinal epithe- stroma, whereas in the secretory phase intense immuno-
lium, stroma, and luteal cells. The angiotensinogen pres- reactivity was seen in the perivascular stromal cells
ence appears to be greater in preovulatory follicles than in around the endometrial spiral arterioles.
atretic follicles. ANG II has been found in human follicu- IV) Angiotensin receptors. Radioligand binding as-
lar fluid (124, 412). Phillips et al. (546) reported that the says were used to demonstrate for the first time radioli-
ovary contained the fourth highest level in 13 tissues gand binding to an ANG receptor in uterine tissue (413).
examined. In addition, the first study to demonstrate ANG II receptor
IV) Angiotensin receptors. The presence of AT1A subtypes showed that the human uterus contains primar-
mRNA but not AT1B mRNA could be demonstrated in the ily the AT2 receptor subtype (771). ANG II receptors are
mouse ovary by Burson et al. (68). For the most part, also present on uterine glands and at a low level in the
follicles that contain ACE also contain ANG II receptors. endometrium of the rat (668). Similar data were provided
In the rat, the follicular ANG II receptors are of the AT2 for the mouse where ANG II receptors are abundant in the
subtype and are located primarily on the granulosa and mouse uterus and primarily of the AT2 subtype. Interest-
theca interna cell layers of atretic follicles (135, 560, 667); ingly, in homogenates of the mouse uterus, the AT1 re-
bovine ovaries contain also predominantly AT2 receptors ceptor predominates, which could be of vascular origin.
(64, 496). Rabbit ovaries express both AT1 and AT2 recep- Since the connective tissue has been removed in this
tors, with the AT1 receptor being localized to the theca study the authors suggested that AT2 receptor binding
and stroma and the AT2 receptor being expressed on the seen in receptor autoradiographic studies is attributable
granulosa cells (804). In contrast, Feral et al. (194) re- to binding to connective tissue rather than on other com-
ported that only the AT1 receptor subtype was present in ponents of the uterus. Autoradiographic studies in the
the rabbit ovary and that it was localized on preovulatory mouse suggest that cervical AT2 receptor density is very
follicles. Autoradiographic receptor studies indicate that high. Again, as seen in the uterus, homogenates of mouse
the AT2 receptor subtype is the predominant ANG II cervix have relatively low levels of ANG II receptor
receptor subtype in the mouse ovary, with only a low level binding.
of AT1 receptor expression (668). In the sheep uterus, AT1 and AT2 receptors are
B) UTERUS. I) Renin. Renin mRNA has been reported in present in the endometrium and myometrium, respec-
the endometrium, choriodecidua, and the fetal part of the tively (451). In late term pregnant sheep, myometrial AT2
placenta (249) but not in the myometrium (299). Via im- receptors are replaced by AT1 receptors. In humans,
munocytochemistry, Raju and Lee (566) demonstrated ⬃90% of the ANG II receptors in the myometrium of
renin in the human endometrial glandular epithelium. nonpregnant women are of the AT2 subtype (115). The
During late pregnancy, the uterus is also a source of density of the ANG II receptors in the uterus of near-term
plasma prorenin (383). pregnant women decreases by ⬎90%, reflecting more than
II) ACE. The rat uterus expresses a low but detect- a 95% loss of AT2 receptors.
able level of ACE (126), and Moeller et al. (451) found C) OVIDUCT. I) ACE. ACE activity is present in the ovi-
ACE activity in high concentrations in the blood vessels of duct of chicken and pig and is localized in epithelial cells
the pregnant and nonpregnant sheep reproductive system of the oviduct in sheep (198, 451, 456).

II) Angiotensin receptors. Receptors for ANG II are AT2 receptor, since an AT2 receptor antagonist
present in the human fallopian tube (600). While both AT1 (PD123319) inhibited hCG- and ANG II-induced ovulation
and AT2 subtypes are present, the functional response to and oocyte maturation in vitro, as well as ANG II-induced
ANG II, enhancement of tubal ciliary-beat frequency, was estrogen and prostaglandin formation. But others (476,
mediated by the AT1 subtype. Receptor autoradiographic 539) using the same ANG II receptor antagonist, or an
studies of ANG II receptor binding in the mouse oviduct ACE inhibitor were unable to fully replicate the inhibition
indicate that they contain AT2 receptors, but at concen- of ovulation. Steele et al. (677) also saw no impairment of
trations that are considerably lower than in the uterus ovulation in rats that were systemically administered an
(668). ANG II antagonist or an ACE inhibitor. The treatment of
D) FUNCTION. I) Ovary. The RAS has been proposed as a women of child-bearing age for hypertension with the
mediator of ovarian function and follicle maturation. ACE inhibitor enalapril did not affect normal cyclicity of
Mukhopadhyay et al. (468) have shown that prorenin plasma gonadotrophins, gonadal steroids, or plasma pro-
secretion from cultured bovine theca cells can be stimu- renin (715). Life-long application of ACE inhibitors to rats
lated by luteinizing hormone. Hagemann (247) suggested did not impair fertility (787). In contrast to this local
that secretion of prorenin from the ovary into the blood- situation, there was a profoundly reduced ovulation by
stream is unique to humans. This group could also dem- ICV administration of ANG II receptor antagonist or ACE

onstrate that luteinizing hormone stimulates renin activity inhibitor (677).
in the follicular fluid of heifers (248). Also gonadotrophin- II) Uterus. Hagemann et al. (249) suggested that the
induced stimulation of renin synthesis and release from local function of ANG II on the uterus may be to control
theca cells of bovine (63) and monkey follicles (304) has uterine blood flow during pregnancy.
been reported. Gonadotrophins are able to stimulate re- As might be expected, the contractile actions of ANG
nin formation in the corpora lutea of the rat (155). The II in the human uterus are mediated by AT1 receptors
authors suggested that angiogenesis of developing cor- (115, 619). The contractile response of the rat uterus to
pora lutea was due to the activation of the RAS in ovula- ANG II and both AT1 and AT2 receptor density vary con-
tory follicles. However, the report that ANG II receptors siderably over the estrous cycle (668).
are not present on most preovulatory follicles (135) would
argue against a significant direct role of follicular fluid 2. Male reproductive tract
ANG II in this angiogenic process. Moreover, recent ob-
servations suggest that vascular endothelial growth factor In the male reproductive system, local RAS function
is a primary angiogenic factor in the rat corpora lutea is thought to be relevant for fertility. This system is reg-
(199, 668). ulated independently from the plasmatic RAS, and the
Fernandez et al. (196) observed that estrogen con- blood testicular barrier prevents that ACE inhibitors and
centration and renin activity in human follicular fluid AT1 blockers affect fertility.
were positively correlated, and others (305) have reported A) TESTES. A representation of the testicular RAS is
that a high level of prorenin was associated with high shown in Figure 4.
levels of testosterone in human immature follicle. ANG II I) Renin. Renin mRNA was detected in mouse testis
is able to induce estrogen release by in vitro pregnant by hybridization using cDNA and cRNA (173, 179, 522,
mare serum gonadotrophin stimulated immature rat ova- 531) and RNase protection analyses (448). Further studies
ries, suggesting that ANG II promotes follicular matura- (153) have shown the Leydig cells as an origin of this
tion (559). In contrast, Morris et al. (467) suggested that tissue renin mRNA. Renin, ACE, ANG I, ANG II, and ANG
ANG II inhibited estradiol (tonic inhibition by endoge- III were detected by both HPLC and radioimmunoassay in
nous ANG II) and increased progesterone formation in purified Leydig cells from rat (523). Naruse et al. (478) did
human cultured luteinized granulosa cells and also in- provide immunohistological evidence for renin in human
creased testosterone in cultured rabbit theca cells in re- Leydig cells.
sponse to hCG (195). II) ACE. The ACE gene encodes for two ACE pro-
Ovulation induced by pregnant mare serum gonado- teins, the somatic ACE enzyme that has two identical
tropin in either immature rats or a perfused rat ovary lobes and the testicular ACE molecule consisting of a
system was inhibited in the presence of an ANG II recep- single lobe. The testicular ACE mRNA is transcribed from
tor antagonist. This inhibition could be overcome by ad- the ACE gene by the tissue-specific choice of an alterna-
ministration of an excess of exogenous ANG II (539, 544). tive transcription initiation site as well as an alternative
In gonadotropin-treated rabbits, the nonselective ANG II polyadenylation site (291, 293, 367, 707). Bernstein et al.
receptor antagonist saralasin is able to inhibit ovulation (48) have demonstrated that mouse testicular ACE
(589). This effect could not be shown by inhibition of ACE (tACE) is encoded by a smaller mRNA (2,500 bases)
(543). Kuji et al. (366) reported that ANG II facilitates compared with the somatic ACE mRNA species found in
follicular development and ovulation in the rabbit via the other organs such as kidney or lung (4,900 and 4,150

existence of pulmonary ACE in rabbit endothelial cells of

blood vessels in the interstitial tissue of testis by immu-
nohistochemistry. In contrast to this finding, Strittmatter
and Snyder (684) could not detect any existence of ACE in
the interstitial tissue of rat testis.
III) Angiotensinogen, ANG I, and ANG II. Angio-
tensinogen mRNA was detected in testicular tissue in
some species. Dzau et al. (174) showed angiotensinogen
mRNA in mouse testis, whereas in rat testis angiotensino-
gen mRNA was undetectable. This goes along with a
report by Campbell and Habener (74) who could not
detect angiotensinogen mRNA in rat testis using Northern
blotting. Only when using a hybridization technique with
increased sensitivity (268) low amounts of angiotensino-
gen mRNA could be detected in rat testis.
IV) Angiotensin receptors. Targeted deletion of the

AT1B receptor gene in the mouse has shown high AT1B
gene transcription activities in testis (95), including ma-
ture and immature spermatic cells. Kitami et al. (347)
measured expression levels of AT1A and AT1B receptors in
rat testis by PCR and suggested that AT1A mRNA was
predominantly expressed.
Aguilera et al. (7) demonstrated the existence of ANG
II receptors in mature rat and rhesus monkey testis, indi-
cating that ANG II receptors are located on the Leydig
cells. These results were confirmed by demonstrating the
localization of the AT1 receptor in rat Leydig cells by
FIG. 4. RAS in the testis. Location of ANG II forming pathways in
immunofluorescence (743).
Leydig cells. Expression of the alternative testicular isoform of ACE B) EPIDIDYMIS. The concept of ANG pathways and func-
(tACE) in germ cells. tion in epididymis and sperm is shown in Figure 5.
I) Renin. The search for renin mRNA in this organ
bases). Molecular cloning of the human tACE cDNA indi- was negative. Leung et al. (397) have not found any level
cates that the mRNA codes for 732 residues (vs. 1,306 in in rat epididymis using Northern blot and even more
endothelium) (375). tACE is equally active despite the fact sensitive RT-PCR assays.
that it is translated from a shorter mRNA. Oligonucleotide II) ACE. ACE activity was measured in rat epididy-
probes derived from tACE cDNA demonstrated expres- mis (282). Interestingly, epididymal tissue contains both
sion of mRNA only in the testes and not in other organs ACE isoenzymes. The somatic ACE isoform was localized
(772). Thus the tACE is highly tissue specific. Leydig cells in rabbit epididymal blood vessels (45). It could also be
have been initially suggested as the primary source of shown by these authors that epididymal tubular cells
ACE in the testis (523), but further investigations have contained pulmonary ACE, suggesting that spermatozoa
confirmed that germinal cells are the origin of the tACE specifically express tACE. This has been supported by
activity. tACE is expressed at high levels by male germ other findings: when spermatozoa were prevented from
cells during spermiogenesis while somatic ACE is also entering the epididymis by efferent duct legation, ACE
expressed in other testicular cells. The regulation of tACE activity in the epididymis was greatly reduced (783).
is tissue specific. Systemically administered ANG II de- III) Angiotensinogen, ANG I, and ANG II. Angio-
creased ACE mRNA levels in the lung and testis, but tensinogen mRNA was detected via RT-PCR and in situ
unlike the pulmonary ACE activity, the tACE activity hybridization histochemistry in rat epididymal epithelium,
shows negligible changes, suggesting that it is caused by with the highest levels found in the epididymal tubules of
different half-lives of mRNA and/or protein (628). the cauda region (397). Using immunocytochemistry,
The concentration of ACE in the testis is among the these authors localized precursor angiotensinogen pro-
highest in all organs (126). And before washout of seminal tein in caput, corpus, and cauda of rat epididymis. The
fluid, ACE activity is higher in the testis than in epididy- concentrations of ANG I and ANG II are high in the rat
mis and vas deferens, suggesting secretion of ACE into epididymal plasma compared with the concentrations in
seminal fluid (282). tACE activity was measured by Hohl- the rete testis fluid and blood serum (783). Also, the level
brugger et al. (282), and Berg et al. (45) have shown the of ANG II in the luminal fluid of the cauda epididymis was

scopic examination indicated that the binding of radiola-

beled ANG II in the epididymis was associated with
smooth muscle cells.
C) SEMINAL PLASMA AND SPERMATOZOA. I) ACE. High ACE
activity has been determined in human seminal plasma
(739). The soluble ACE in seminal fluid resembles the
detergent-solubilized lung enzyme more than the deter-
gent-solubilized testicular enzyme (150, 180). The active
enzyme in seminal fluid corresponds to the pulmonary
polypeptide (45, 372). These authors suggested that this
seminal fluid ACE may originate from cells of the epidid-
ymal tubules, particularly those of the vas deferens. Via
autoradiographic visualization with [3H]captopril, Stritt-
matter et al. (684) have shown high densities of [3H]cap-
topril over spermatid heads, and in the lumen of seminif-
erous tubules also, the head of the epididymis demon-

strates intense grain density at the luminal surface of the
epithelium with little luminal labeling by rats. The testic-
ular ACE is expressed at high levels by developing germ
cells and is present in mature sperm (774). With the use of
indirect immunofluorescence and immunoperoxidase
methods, tACE was found in the seminiferous tubules of
the testes in spermatocytes containing mature sperma-
tids, and in spermatids within the epididymal tubular
lumen in sexually mature, but not in immature, rabbits
(45), suggesting that the presence of tACE is dependent
on sexual maturation.
FIG. 5. RAS in the epididymis: intraluminal and intracellular gener-
II) Angiotensin receptors. AT1 receptors were found
ation of ANG II in the epididymis. Paracrine and autocrine secretion of in primary spermatogonia and spermatid tails of rat testis
ANG II is mediated via the AT1 receptor. AT2 receptors may modulate by Vinson et al. (743). These authors were able to confirm
basal cell proliferation and differentiation. tACE may play an important
part in local modulation of fertility, but its exact role is unclear.
this finding in ejaculated rat and human free swimming
[Adapted from Zhao et al. (808).] sperm. Interestingly, they did not find any immunofluo-
rescent activity from the spermatozoa in the lumen of rat
epididymis and from sperm isolated from the epididymis.
markedly reduced after efferent duct ligation (783, 808). By targeting deletion of AT1B receptor gene in the mouse,
With immunohistochemical staining, Zhao et al. (808) de- Chen et al. (95) have shown high AT1 transcriptional
tected ANG II in rat epididymis with the highest level in activities in mature and immature spermatic cells, sug-
the basal cells of the cauda. The same authors suggested gesting that AT1A can take over specific functions in these
a potential of the epithelial cells to secrete ANG II, since knock-out animals or that other ANG receptors are in-
ANG II could be detected by radioimmunoassay in the volved in this process.
supernatant of cultured endothelial cells. D) GLANDULA VESICALIS. I) ACE. High ACE activity has
IV) Angiotensin receptors. Leung et al. (392) pro- been determined in human vesicula seminalis (739).
vided evidence for the existence of ANG receptors in rat E) PROSTATE. I) Renin. Renin mRNA is present in mouse
epididymis. Both AT1 and AT2 were detected; however, prostate, and the human prostate shows a positive signal
the immunostaining intensity for AT1 receptors was found after renin immunohistochemistry (478).
to be stronger than that for AT2 receptors, and the immu- II) ACE. High ACE activity has been determined in
nostaining for both receptors observed in the fully mature human benign prostatic hyperplasia, whereas normal
rat epididymis was much more intense than that observed prostates apparently have low enzymatic activity (282,
in younger stages. The immunostaining was predomi- 739, 802). Other authors (735) have found higher levels in
nantly localized in the basal region. Grove and Speth (242) the lateral and posterior prostate compared with ventral
have shown that rat epididymis contains functional ANG prostate in rat, but the activity was still much lower than
II receptors. Also, Vinson et al. (743) have found AT1 that in epididymis.
receptors in epithelial tissue of rat epididymis. Autoradio- III) Angiotensin receptors. Dinh et al. (164) reported
graphic analysis showed the presence of ANG II receptors that in human prostate ANG II receptors were of the AT1
also in the rhesus monkey epididymis (7). Light micro- subtype and localized predominantly to periurethral stro-

mal smooth muscle, and the density of ANG II binding AT1 and AT2 receptor concentration of rat testis with
sites was markedly reduced in benign prostatic hyperpla- predominant occurrence of AT1 receptors measured by in
sia. It has been suggested that this may be due to receptor vitro autoradiography (275). The concentration of rat AT1
hyperstimulation by increased local levels of ANG II in and AT2 receptors at protein level is dependent on the
benign prostatic hyperplasia. developmental stage. Total ANG II receptor binding (pre-
F) VAS DEFERENS. I) ACE. Immunohistochemistry dominantly AT2 receptor) in the testis was highest at 1
showed strong staining for somatic ACE in cells of the vas day of age and decreased gradually thereafter, and the
deferens in both young and adult rabbit (45), whereas 4-wk-old rat testis contained almost exclusively AT1 re-
other authors could only describe low ACE activity (735). ceptors (334).
G) SEMINAL VESICLES. I) ACE. Only low ACE activity was II) Epididymis. Anion and fluid secretion is stimu-
found in seminal vesicles (735). lated by a number of peptide hormones, including ANG
H) FUNCTION. I) Testis. After hypophysectomy renin lev- (782). Previous electrophysiological studies demon-
els in the rat testis decreased significantly, whereas strated a higher potency of ANG II on the basolateral
plasma renin was slightly increased (480), suggesting an surface in eliciting transient increases in short-circuit cur-
alternate regulation of the circulatory and testicular RAS. rent when added to the basolateral as well as to the apical
The immunohistochemical renin staining of rat Leydig surface of rat epididymal epithelium. ANG II secreted

cells was suppressed or abolished by hypophysectomy from the basal cells may exerts its effect on electrolyte
and estrogen treatment and was reduced by gonadotro- transport by acting on ANG II receptors on the basolateral
phin stimulation (520, 525). The treatment of cultured membrane of the principal cells, which are largely respon-
mouse Leydig tumor cell line with human chorionic go- sible for the electrolyte transport. Electrophysiological
nadotropin or bovine luteinizing hormone results in a high studies using the short-circuit current technique demon-
increase of renin activity (521). It has to be noted in this strated a stimulatory effect of basolaterally applied ANG
context that almost all renin activity is confined inside the II on the epididymal electrogenic ion transport, suggest-
cell with only 1–2% of its total activity being present in the ing AT1 as the target receptor (394).
culture medium. Okuyama et al. (514) have shown that III) Seminal plasma and spermatozoa. ACE enzyme
treatment with hCG increases the plasma renin activity in activity is low in immature animals and increases with the
internal spermatic vein without an increasing of the sys- onset of sexual maturity (126, 314). The ACE activity in
temic plasma renin activity. The authors could not ob- semen is enhanced by sexual stimulation (282, 313) but is
serve any release of renin from Leydig cells into testicular normal in oligospermic men (281). A role of the tACE in
blood flow under basal conditions. capacitation has been suggested by several authors (211,
There is a positive correlation between testosterone 658). Previous reports have suggested that ACE is re-
and plasma renin activity in the internal spermatic vein of leased during sperm capacitation (356), which was con-
humans after hCG treatment (525). firmed after exposure to ACE inhibition that affected the
Treatment with hCG or bovine luteinizing hormone acrosome reaction and the ability of human sperm to
increased also the ANG production in a cultured mouse penetrate an egg (212).
Leydig tumor cell line (521). It is noteworthy that the Knockout technology was used to investigate the role
major portion of ANG II is released in the culture medium of ACE in male fertility (361). Hagaman et al. (246) have
and the majority of ANG I was present in the cell. To- shown with this method that although male mice lacking
gether with the mentioned intracellular presence of renin ACE were infertile, the number of sperm, the viability,
and ACE (523), this supports the possibility of intracellu- motility, capacitation, and induction of the acrosome re-
lar formation of ANG II. action were normal. Despite these normal functional pa-
Hirai et al. (275) could verify that the AT1 and AT2 rameters, very few sperm are found in the uterine tube
mRNA gene expression in rat testis is pituitary dependent. region, and even those sperm that reach the oviductal
After hypophysectomy, the receptor gene expression was ampulla are less likely than normal sperm to fertilize eggs
significantly increased. Human chorionic gonadotrophin because of their reduced capacity for zone binding. The
and human menopausal gonadotrophin reduced the AT1 authors suggested that tACE may play a role for the
and AT2 mRNA gene expression. Furthermore, the AT2 detachment of sperm from the oviduct epithelium and/or
mRNA expression in rat testis is dependent on develop- other structures in the female reproductive tract at capac-
mental stages, since Northern blot analysis showed that itation. Esther et al. (189) used targeted homologous re-
mRNA expression of both AT1 and AT2 types decreased combination to introduce a modified ACE allele into a
with age (334). Aguilera et al. (7) reported also a decrease mouse line. Homozygous male mice have markedly re-
in ANG II binding during development and that in imma- duced blood pressure, severe renal disease, and reduced
ture rat a high proportion of ANG II receptors in the testes fertility, however, corresponding to no defect in sperm
are located in nondifferentiated mesenchymal cells of the number, morphology, or motility. Corresponding to this,
interstitium. Hypophysectomy led to a marked increase in Ramaraj et al. (567) used transgenic techniques to gener-

ate mice with exclusive expression of tACE using ACE vascular beds, and these values were compared with
knockout mice as a background. These animals express plasma renin activity. The data provide a higher level of
ACE only in sperm, since a sperm-specific promoter was ANG I in venous plasma compared with the level in
used to direct expression of tACE. The background ACE arterial plasma, independent of plasma renin activity. This
knockout mice lack both isoenzymes (somatic ACE and is seen as evidence for local ANG I release; however, the
tACE) and exhibit low blood pressure, kidney dysfunc- concentration difference could also be caused by a higher
tion, as well as male infertility. The transgenic “rescue” by local renin activity. Unfortunately, there are no data avail-
the selective tACE overexpression resulted in normalized able that could be considered as evidence for the local
fertility. The male fertility defect does not appear to be synthesis of angiotensinogen.
related to the low levels of ANG II expected in the ACE-
deficient mouse. Angiotensinogen-deficient mice, which 4. Angiotensin receptors
cannot synthesize ANG II, do not have any defects in male
Radioligand binding studies were performed on cul-
fertility (246, 339). Nagata et al. (477) have also investi-
tured human primary keratinocytes and showed binding
gated a mouse line lacking angiotensinogen and sug-
to ANG II. Interestingly, the AT1 and AT2 receptor antag-
gested that female-derived ANG I is also not an essential
onists losartan and PD123177 are not able to displace the
substrate for tACE.
radioligand. Thus the keratinocytes seem to express an

There are suggestions for a function of AT1 receptors
ANG II receptor subtype distinct from AT1 and AT2 re-
as determinants of sperm motility, since ANG II increases
ceptors (673).
both the percentage of motile sperm and their linear
velocity and AT1 receptor antagonists inhibit this action 5. Function
of ANG II (743).
A) WOUND HEALING AND REPAIR. Increased ANG II levels
were measured during wound healing in rat skin (243,
E. Skin
345), but this is not conclusive evidence for local produc-
tion because ANG II could also be taken up from plasma
1. Renin
into the tissue. Previous studies described a proliferative
Northern blot analysis showed renin mRNA expres- and antiproliferative effect of ANG II in the skin which
sion in murine subcutaneous tissue but not in murine appear to be mediated by AT1, AT2, and non-AT1, non-AT2
dermis and epidermis (653). receptors (105, 485, 524, 673, 681).
Quantitative autoradiography demonstrated that the
2. ACE expression of ANG II receptors was significantly en-
hanced during experimental wound healing. Young rat
One study (685) could detect large amounts of ACE
skin normally contains mainly AT1 receptors, but during
in subcutaneous tissue of the rat by quantitative autora-
experimental wound healing a selective and localized in-
diography, but it is unclear which cell type expresses ACE
crease in expression of AT2 receptors occurs (745). This
in this tissue. It could also be expressed by vascular
study suggested skin fibroblasts as the primary target
endothelial cells or be taken up from the circulation. No
cells for ANG II. Other investigators (345) have found
signal for ACE was detected in the dermal and epidermal
significant decreases in the number of AT1 receptors and
layers of rat skin. Steckelings and co-workers (675)
a modest but not statistically significant appearance of
pointed out that the absence of ACE in this region as well
AT2 receptors in adult rat skin during wound healing. This
as in the subcutaneous tissue may not present a problem
is not necessarily a contradiction and could be an indica-
for local ANG formation, since the skin is abundant in
tion for the importance of the proportion or balance of
mast cells and that mast cell-derived chymase may act as
these two receptors. Abiko et al. (3) have shown that an
a substitute for ACE (217, 675). Moreover, more recently,
immediate and transient reduction in ANG II receptor
it was shown that mast cells are an additional source of
expression occurred after wounding rat skin, followed by
renin synthesis (654), which could be of relevance for the
an increase in the number of the receptors that was
RAS activity and regulation at the tissue level, because of
maintained for 5–7 days, and that the receptors were
the ubiquity of mast cells in tissues.
predominantly of the AT1 receptor subtype. In a cutane-
ous repair model, Sun et al. (686) have shown that the
3. Angiotensinogen, ANG I, and ANG II
appearance of myofibroblasts is associated with ANG II
There is only one study suggesting local production generation which regulates fibrogenesis by AT1 receptor
of ANG I and ANG II in the skin of captopril-treated pigs binding. In rat skin slices, ANG II binding to AT1 receptors
(130). ANG I and ANG II levels in the presence of constant increases inositol phosphate production, while binding to
intracardiac infusion of 125I-ANG I and 125I-ANG II were AT2 decreases inositol phosphate production; thus both
measured in arterial and venous plasma across cutaneous receptors play opposite roles (243). It has to be noted that

it was unclear in the two former studies in which cell type within the islets of human pancreas (695). Renin protein was
the ANG II receptor regulation and signal transduction found in the beta cells of the human islets of Langerhans and
occurred (243, 686). Further investigation has suggested a in endothelial cells of the pancreatic vasculature.
mitogenic effect of ANG II of keratinocytes via a non-AT1, B) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen
non-AT2 ANG receptor (673). ANG-(1O7) binding sites mRNA and angiotensinogen protein were found in canine
were also characterized in human skin fibroblasts (493). pancreas (93). In contrast, Campbell and Habener (74) did
not find angiotensinogen mRNA in rat pancreas. The pres-
ence of ANG II was reported in canine pancreas by Chap-
F. Digestive Organs
pell et al. (93). Also in mouse ANG II-like immunoreactiv-
ity was localized predominantly in the endothelial cells of
1. Salivary glands pancreatic blood vessels and the epithelial cells of pan-
A) RENIN. The salivary gland of some mouse strains creatic ducts from a subgroup of the vessels and ducts,
expresses significant amounts of renin. It is interesting to and with lower intensity in acinar cells and in smooth
note that renin production in the salivary gland is partic- muscle layers overlying the pancreatic ducts and blood
ularly high in mouse strains that contain two renin genes vessels. However, no ANG II immunoreactivity was de-
(Ren-1 and Ren-2), which are the result of a gene dupli- tected in the islet cells (395).

cation that occurred during evolution (2). Both genes are C) ANGIOTENSIN RECEPTORS. The majority of ANG II binding
expressed in most mouse organs such as kidney (204), sites in the canine pancreas could be classified as AT2 sub-
whereas only Ren-2 is expressed in mouse salivary types, although AT2 subtype was also detected (92). The
glands, particularly in the submandibular gland (179, 205). same study has reported that the binding sites were local-
Although the functional significance of this gene duplica- ized over islet cells, acinar and duct cells, as well as the
tion is unknown, the study of two-gene mice provided an pancreatic vasculature. ANG II binding sites were also found
excellent opportunity to investigate the molecular basis in islet cell membranes and the exocrine pancreas of the rat
of tissue-specific renin gene expression, and the func- (224). Another study has reported predominant distribution
tional role of the Ren-2 gene has been studied extensively of AT1 and AT2 receptor subtypes in the endothelia of the
in transfected cells (529), transgenic mice (472), and blood vessels and the epithelia of the pancreatic ductal
transgenic rats (471). The latter model is of particular system of rat and mouse (393). The presence of the AT2
importance in this context, since the transgenic rats with receptor in the beta cells of the human islets of Langerhans,
Ren-2 expression suffer from fulminant hypertension and and in endothelial cells of the pancreatic vasculature, was
severe end-organ damage. The gene duplication is specific demonstrated by Tahmasebi et al. (695).
for the mouse, and expression of the rat and human renin D) FUNCTION. The pancreatic RAS appears to regulate
genes correlates (159) with that of the mouse Ren-1 gene. secretion of pancreatic hormones. Elevated plasma so-
B) ANGIOTENSINOGEN. Low angiotensinogen mRNA levels dium concentration resulted in depression of the binding
were detected in the CD-1 male mouse and the C57BL/6 affinity and capacity, whereas sodium depletion elevated
mouse (701) submandibular gland, but like renin mRNA, both binding affinity and capacity of ANG II binding sites
angiotensinogen mRNA could not be detected in rat sub- in rat pancreas (224). In a rat pancreatic acinar cell line
mandibular gland (174). (AR4 –2J), ANG II stimulated via AT1 receptor a dose-
C) RECEPTORS. Using a radioligand binding assay, Mat- dependent release of amylase (97).
subara et al. (442) found mainly AT1 receptor subtypes in In rat pancreas, chronic hypoxia caused a marked
rat submandibular organ. increase in angiotensinogen both at the protein and gene
D) FUNCTION. The ultimate role of renin and other com- levels and an increase in AT1B and AT2 receptor mRNA
ponents of the RAS in the submandibular gland are not when compared with that in the normoxic pancreas (91).
known. It has been associated with mediation of the “fight ANG II infusion induced a dose-dependent reduction
and flight” reaction. Renin activity in the salivary glands in both whole pancreatic and islet blood flow in rats and
increases with stress, pituitary hormone release, and ad- points to a pivotal role of islet blood perfusion for an
renergic stimuli and is associated with aggressive behav- adequate insulin release (79). More recent studies suggest
ior in mice (557, 775). There have also been indications of a role for ANG II-induced apoptosis of pancreatic acinar
a role in saliva production, since ACE inhibition increases cells in pancreas fibrosis mediated by AT1 receptors
overall saliva secretion of humans but does not affect its (763). This finding and the overall functional relevance of
composition (483). the tissue RAS in the pancreas awaits further study (396).
2. Pancreas 3. Stomach
A) RENIN. Renin mRNA was detected in the connective A) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen
tissue surrounding the blood vessels and in reticular fibers mRNA was found in rat stomach (74). Ludtke et al. (422)

plasma membrane and the intestinal brush border of the

rat (764). ACE immunoreactivity was detected in human
small intestine blood vessels (microvascular endothelium
was strongly labeled) and the absorptive epithelial cells of
intestinal mucosa, especially in microvilli and brush bor-
ders (62). Costerousse et al. (110) reported that in the rat
intestine, ACE mRNA levels and ACE activity were very
high at birth and then decreased dramatically during the
next 2 wk. ACE activity was reported also in the brush-
border membrane from the small intestinal epithelium of
the common grackle (679). ACE2 mRNA expression is
ubiquitously found including the intestine (251); however,
systematic expression analysis revealed a remarkable sur-
face expression of ACE2 protein in enterocytes of the
small intestine (251).
C) ANGIOTENSINOGEN. Angiotensinogen mRNA was de-

tected in mesentery but not in small intestine of rat (74).
D) ANGIOTENSIN RECEPTORS. AT2 receptor mRNA and pro-
tein were characterized on cultured rat intestinal epithe-
lial cells (661). The distribution of ANG II receptor was
localized by Duggan et al. (171) via in vitro autoradiogra-
phy. ANG II receptors were most abundant in the colon,
followed by the ileum, duodenum, and jejunum. Within
each segment of the intestine, specific ANG II binding
sites were localized exclusively to the muscle layer. Sechi
et al. (633) detected by autoradiography AT1 and to a
lesser extent AT2 receptors in rat intestine. Specific bind-
FIG. 6. RAS in the intestinal tract. Interaction with plasma RAS and
ing was moderately abundant in the mucosa and the
RAS in nerve endings. muscularis of both jejunum and ileum, whereas no bind-
ing was present in the submucosa and the serosa. In the
colon, binding was significantly more abundant in the
have reported phasic and/or tonic responses of human muscularis than in the mucosa. Hosoda et al. (288) could
gastric smooth muscle to ANG II which often exceeded clearly demonstrate the distribution of AT1 immunoposi-
the maximum acetylcholine-induced activation. tive cells in enteric nerves and moderately in surface
B) FUNCTION. Cullen et al. (123) have found that capto- epithelial cells of guinea pig distal colon. Functional AT1
pril alleviated the systemic acidosis and the stress ulcer- receptors were shown by Schinke et al. (618) in the rat
ation produced by canine hemorrhagic shock. Because ileum and duodenum
during shock captopril enhanced blood flow to the small E) FUNCTION. At low physiological doses, ANG II stimu-
intestine, pancreas, liver, and spleen, but not to the stom- lates jejunal sodium and water absorption in adrenalec-
ach, the authors concluded that alleviating systemic aci- tomized rats, whereas at a high dose the peptide inhibited
dosis was mediated through enhanced perfusion of other absorption (400). However, the stimulation of jejunal wa-
visceral organs. ter absorption was abolished in peripherally sympathec-
tomized rats (400). In vitro study showed that mucosal
4. Intestine additions of ANG II were more or less able to stimulate
jejunal sodium and water absorption than serosal addi-
ANG pathways in the intestinal tract are represented tion (399). Also, ANG III is able to stimulate rat jejunal
in Figure 6. fluid absorption. This effect can be blocked by guanethi-
A) RENIN. Renin gene expression was found in the in- dine, phentolamine, and prazosin, suggesting that ANG
testine of human and mouse (636). III-increased intestinal absorption is secondary to the re-
B) ACE. ACE has been localized in the brush border of lease of norepinephrine from sympathetic nerves in the
human jejunum (678). In the rat, the highest ACE mRNA, jejunum (398). The same author has reported in another
ACE protein, and activity within the intestine were found study that ANG II was able to enhance absorption in
in the brush-border membrane fraction in the proximal to isolated rat jejunum in the presence of prazosin (399).
midregion of the small intestine (186, 806). ACE activity This is contradictory to the hypothesis of involvement of
was highly enriched on both the intestinal vascular the sympathetic nervous system in mediating ANG II-

stimulated fluid absorption. Cox et al. (116) have shown inducing peristaltic waves. In the ileum, the contraction is
that ANG II, if applied to the basolateral surface, elicited caused by the longitudinal smooth muscle and is medi-
increases in short-circuit current in preparations of rat ated by the AT1 receptor.
jejunum and decreases in the descending colon. They Jaszewski et al. (317) have reported that mucosal
have further shown that the response was not affected by levels of ANG I and II were elevated in patients with
␣- or ␤-adrenoceptor antagonists but by a chloride chan- Crohn’s colitis versus normal subjects and other forms of
nel blocker and that the increase/reduction in short-cir- colitis and that mucosal levels of ANG I and ANG II
cuit current elicited by ANG II in jejunum/colon was correlated well with the degree of macroscopic inflamma-
inhibited by both piroxicam and indomethacin. Jin et al. tion in Crohn’s disease.
(320) detected that in rat jejunum the low-dose ANG The RAS is highly activated during hyovolemic shock
II-stimulated fluid and sodium absorption was blocked and has been suggested to be involved in the pathophys-
completely by the specific AT2 receptor antagonist iology of the markedly deteriorated splanchnic circula-
PD123319 but was unchanged by losartan. Conversely, tion seen in this condition. Aneman et al. (16) detected
high-dose ANG II inhibition of absorption was blocked by that the downregulation of mesenteric oxygenation and
losartan but not by PD123319. The ANG II-mediated so- duodenal mucosal function during hypovolemia in pigs
dium and fluid absorption involved cGMP formation, and can be prevented by administration of enalaprilat,

the high-dose inhibition via the AT1 receptor is both neg- whereas guanethidine is ineffective in this respect. The
atively coupled to cAMP and increases jejunal PGE2 pro- authors concluded that this might be of clinical interest to
duction. A comparison between SHR rats and normoten- support mesenteric perfusion and organ function in hy-
sive controls has shown that SHR possess an enhanced povolemia (16). Also, AT1 receptor blockage ameliorated
intestinal fluid absorption both in hypertensive adults and mesenteric and particularly jejunal mucosal hypoperfu-
in normotensive young SHR (170). ANG II was also able to sion during hypovolemia in pigs (17). Furthermore, mor-
enhance water absorption and antagonized the secretory tality in conjunction with acute hypovolemia and retrans-
effect of vasoactive intestinal polypeptide (VIP) in the fusion could be completely avoided. Oldner et al. (517)
ileum similar to norepinephrine (49). The increased rat reported that ANG II receptor antagonism increases gut
jejunal fluid absorption after extracellular fluid reduction oxygen delivery but fails to improve intestinal mucosal
is not affected by adrenalectomy, but is abolished by acidosis in porcine endotoxin shock. Tadros et al. (694)
nephrectomy, captopril, prazosin, and peripheral sympa- detected that ANG II appears to play a pivotal role in the
thectomy, suggesting that ANG II is generated after extra- burn- and endotoxin-induced intestinal ischemia and
cellular fluid reduction and increases jejunal fluid absorp- reperfusion injury in pigs, with subsequent increases in
tion by facilitating the release of norepinephrine from permeability and bacterial translocation and that admin-
enteric sympathetic nerves (78, 399, 400). Serosal addition istration of the ANG II receptor antagonist DuP753 after
of ANG II produced a concentration-dependent short- birth significantly reduces the extent of these events.
circuit current in guinea pig distal colon (288). The au-
thors reported that the ANG II evoked responses were 5. Colon
mainly due to Cl⫺ secretion and mediated by the AT1
A) ANGIOTENSINOGEN. Angiotensinogen mRNA was de-
receptor. Hatch et al. (263) reported that the enhanced K⫹
tected in rat large intestine (74).
secretion in distal colon of rats with chronic renal failure
B) FUNCTION. It has been demonstrated that ANG II
was mediated by AT1 receptors, since the secretion was
stimulated fluid transfer and sodium transport in seg-
reversed to an absorptive flux by losartan treatment, and
ments of isolated rat proximal colon. Further investiga-
rats with chronic renal failure exhibit twofold higher ANG
tion suggested that ANG II stimulated a coupled NaCl
II binding sites in distal colon compared with controls.
transport (145). In rat distal colon, ANG II can stimulate
Yoshioka and co-workers (805, 806) detected that the
intestinal water transport via an electroneutral mecha-
peptidase activity of the rat brush-border membrane for
nism already at subpressor doses; this is a specific effect
specific peptide sequences can be inhibited by ACE inhi-
and in contrast to aldosterone which stimulates intestinal
bition. The authors suggested that intestinal brush-border
sodium and water transport by electrogenic mechanisms
membrane ACE functions as a digestive peptidase. This
(402) involving the epithelial sodium channel (47).
group also suggested (186) that ACE is an important
intestinal dipeptidyl carboxypeptidase, participating in
the digestion and assimilation of dietary peptides in rats G. Sensory Organs
(186). Suzuki et al. (690) detected that a diet high in
1. Eye
proline is particularly effective in increasing intestinal
ACE mRNA and activity in rats. The presence of a local RAS in the eye has been
ANG II causes a contractile response in the rat ileum suggested by studies demonstrating the expression of all
but not in the duodenum (617), pointing to a role in components of the system in ocular tissue. Wagner et al.

(752) have demonstrated that the mRNA of renin is ex- less than brain blood flow. Unlike this finding, Quirk et al.
pressed in the retinal epithelium, whereas angiotensino- (563) have found a cochlea blood-flow autoregulation in
gen and ACE mRNA were found both in the retinal epi- rats mediated directly by ANG II. Intra-arterially infused
thelium as well as in the neural retina of the eye. These ANG II produced an initial increase in cochlear blood flow
data suggest that the machinery for ANG production is that is followed by a slow steady return to baseline,
present locally and not only restricted to vascular struc- despite sustained elevations in systemic blood pressure.
tures in the eye. Evidence that the RAS is also expressed Furthermore, a direct infusion of ANG II in the anterior
at the protein level has been provided by Sramek et al. inferior cerebellar artery of rats (563) results in significant
(670, 671) who used immunohistochemistry against pro- reduction in cochlear blood flow without changes in sys-
renin and angiotensinogen to describe prorenin in the temic blood pressure. This effect can be abolished by
ciliary body and angiotensinogen in the pigmented ciliary ANG II receptor antagonism. Another study (107) inves-
epithelium. tigated the role of ANG IV in the cochlear blood flow in
The question of whether the presence of the RAS guinea pigs. Anterior inferior cerebellary artery infusion
components also leads to local production of ANG pep- of ANG IV increased in a dose-dependent manner the
tides has been answered by Danser et al. (131) who cochlear blood flow with little change in mean arterial
suggested that the ocular ANG concentrations are too blood pressure.

high to be caused by blood-borne peptides. The role of ANG II in cochlear blood flow, however,
A) FUNCTION. Whereas the presence of the components appears to be species specific and is not completely un-
of the RAS has been well documented in the eye, little is derstood. This notion is based on results from an inves-
known about its local function. Since ANG II receptors tigation that has shown that ICV-administered ANG II
have been detected primarily on retinal blood vessels, it leads to blood pressure elevation and that cochlear blood
has been suggested that the ocular RAS may be involved flow was more highly correlated with blood pressure in
in the regulation of ocular vascular tone. Apart from this the guinea pig than in the rat in this setting (209).
aspect, the ocular RAS may be involved in the regulation A pathophysiologically oriented explanation of the
of aqueous fluid since local application of ACE inhibitors controversy has been offered by Goldwin et al. (236). The
influences aqueous fluid production. A recent report sug- discovery that during noise exposure insufficiencies in
gested that the ocular RAS may be relevant for maintain- cochlear blood flow may cause temporary or permanent
ing normal secretory function of epithelial cells in the threshold shifts suggests that vasoactive substances in-
ciliary bodies (125). In this study, ANG II was defined as cluding ANG II may mediate this effect. By pretreatment
a secretagogue, leading to cell volume loss in cultured with ANG II receptor antagonists, both cochlear micro-
nonpigmented epithelial cells derived from human ciliary circulation and auditory sensitivity were measured during
body. This process is antagonized by losartan, suggesting noise exposure. Results showed that pretreatment pre-
that ANG receptor blockade could be a new pharmaco- vented this noise-induced microcirculatory ischemia and
therapeutic approach in the treatment of glaucoma. The preserved auditory sensitivity at the low frequencies
pathophysiological role of the local RAS in the eye ap- tested (236). In summary, the evidence for the existence
pears of special clinical importance since it has been of a local cochlear RAS is scarce and needs further anal-
linked to diabetic mellitus (682). ysis. Moreover, it is not at all clear whether local produc-
tion of ANG II in the cochlea plays a significant role for
2. Cochlea the effects reported so far.
There are suggestions of an influence of ANG II on

H. Lymphatic Tissue
cochlear blood flow, which very well could be a second-
ary effect. Wright et al. (784) exposed guinea pigs to a
1. White blood cells
120-dB white noise for 30 min. The result was a fourfold
elevation in plasma concentration of ANG II. A second A) MONOCYTES. I) Renin. Renin mRNA was detected in
experiment in the same study showed that an intra-arte- rat peritoneal macrophage/monocyte cells (308). Also,
rial injection of ANG II (at concentrations comparable to renin-like immunoreactivity was detected within these
those measured after noise exposure) increases the sys- cells by the same authors, suggesting that monocytes may
temic blood pressure and cochlear blood flow. This find- be a source of tissue renin in some pathological condi-
ing suggests that elevated blood pressure, caused by noise tions. Dezso et al. (157) detected renin protein in rat and
exposure and mediated by ANG II, increases the cochlear mice alveolar macrophages and monocytes by high-pres-
blood flow, and it was suggested that this is due to a lack sure liquid chromatography.
of a cochlear blood-pressure autoregulation in guinea II) ACE. ACE mRNA was found in human mono-
pigs. Kawakami et al. (337) showed that cochlear blood cytes, but only after 4 days in culture (23). Prominent
flow of guinea pigs may have some autoregulation but was staining for ANG II was found in human mononuclear

leukocytes (348). These authors have also detected ANG B) ANGIOTENSIN RECEPTORS. ANG II receptors were not
I staining, but the signal was less pronounced than for detected in thymus sections from rats or mice, or on
ANG II. Rat and mouse macrophages and monocytes isolated rat thymocytes (86). But in newborn rats, Correa
contain ANG I and ANG II as well (156). et al. (108) have detected AT1/AT2 receptors (15%/85%) in
III) Angiotensin receptors. Shimada and Yazaki the trabecula. The binding sites were no longer detected
(647) demonstrated ANG II binding sites in human mono- in 4- and 8-wk-old rats.
nuclear leukocytes via autoradiography. ANG II binding
sites were reported on guinea pig macrophages (708),
I. Adipose Tissue
which were found responsible for ANG II incorporation
by these cells. Finally, Simon et al. (657) reported that
ANG II binding to human mononuclear cell is not easily Apart from its presence in white adipose tissue
reversible and is poorly inhibited in a competitive man- where the local RAS may play a role in the pathogenesis
ner, suggesting that endocytosis occurs. of syndrome X, RAS components have also been detected
Kim et al. (340) reported that ANG II increases mono- in brown adipose tissue located adjacent to the adventitia
cyte binding to human as well as rabbit aortic endothelial of blood vessels, where it could provide an interface with
cells, suggesting a role in arteriosclerosis. the vascular RAS.

B) GRANULOCYTES. Human neutrophils possess the ability
to convert ANG I to ANG II via cathepsin G, a lysosomal 1. Renin
serine protease (349). Reilly et al. (571) reported a rapid Renin mRNA was found in adipose tissue of obese
conversion of ANG I to ANG II by human neutrophil humans (335). Renin activity was localized in interscapu-
cathepsin G and human skin mast cell chymase. And lar brown adipose tissue, especially in adipocytes, which
Wintroub et al. (780) demonstrated that angiotensinogen is not decreased after bilateral nephrectomy (643). Renin
is also cleaved by cathepsin G, suggesting that a human and all other components (angiotensinogen, renin binding
granulocyte-angiotensin system does not require renin or protein, ACE, and AT1 receptors) that are necessary to
ACE. Human polymorphonuclear leukocytes showed very form a local RAS were found in human preadipocytes
little staining for ANG II (348), whereas ANG II can induce (620), in human adipose tissue, and in cultured human
neutrophil chemoattractant release from human and bo- adipocytes (183, 184).
vine cultured endothelial cells (191) pointing at local
regulation. 2. ACE
2. Spleen ACE mRNA was found in both human subcutaneous

and extraperitoneal adipose tissue, especially in adipo-
A) RENIN. With the use of RNase protection assays, renin cytes (328). Also, Karlsson et al. (335) have detected ACE
mRNA was detected in rat spleen. Ekker et al. (179) have mRNA in adipose tissue of obese humans. ACE synthesis
also found renin gene expression in rat and mouse spleen by at protein levels was detected in human preadipocytes
primer-directed enzymatic amplification of cDNAs. (620).
B) ANGIOTENSINOGEN. Angiotensinogen mRNA was de-
tected in rat spleen (74). 3. Angiotensinogen, ANG I, and ANG II
C) ANGIOTENSIN RECEPTORS. Binding sites for ANG II were
localized in the red pulp of the spleen of rats and mice by Angiotensinogen mRNA was identified in periatrial
quantitative autoradiography (86). ANG II binding sites and periaortic brown adipocytes and in fibroblast-like
were also localized on isolated rat spleen cells. Tsutsumi cells of periaortic connective tissue and mesentery of rat
et al. (722) showed that the binding sites for ANG II are (73, 84). By Northern blot analysis, Karlsson et al. (335)
attributable to the AT1 receptor subtype. However, mouse demonstrated angiotensinogen gene expression in adi-
spleen lymphocytes seem to posses both AT1 and AT1 pose tissue from adipose humans. Slices from interscap-
receptor subtypes (368). ular brown adipose tissue are able to release immunore-
3 active ANG II peptides (643). Schling et al. (620) showed
D) FUNCTION. ANG II significantly enhanced the [ H]thy-
midine incorporation into DNA of mouse splenocytes that ANG II was secreted both by undifferentiated human
(368). The stimulatory effect was only blocked when lo- preadipocytes and immature adipocytes, and its produc-
sartan or PD123319 was added together with ANG II. tion was significantly elevated in differentiated cells.
3. Thymus 4. Angiotensin receptors

A) RENIN. Renin gene expression was found in rat and The receptor subtype that is present most abundantly
mouse thymus by primer-directed enzymatic amplifica- in both white and brown adipose tissue is the AT1 recep-
tion of cDNAs (179). tor subtype. Mice adipose tissue expresses predominantly

AT1A subtypes (68). Crandall et al. (121) localized AT1 blood pressures as a background, the scientists generated
receptor protein in rat epididymal, mesenteric, and retro- transgenic mice with angiotensinogen expression re-
peritoneal adipose tissue and human omental and subcu- stricted to adipose tissue. The animals showed circulating
taneous adipose tissue. It is also notable that in human angiotensinogen, increased fat mass, normotension, and
preadipocytes there was a high-affinity ANG II binding restored renal function (438). In addition, transgenic mice
site of the AT1 subtype (121). Rat white adipose tissue derived from wild-type mice and designed to overexpress
contained a greater number of ANG II binding sites than angiotensinogen only in adipose tissue demonstrated ele-
brown adipose tissue and both present the AT1 subtype vated plasma angiotensinogen and developed hyperten-
(83). sion (438). In another study, the authors could demon-
strate by studying angiotensinogen-deficient and wild-
5. Function type mice that angiotensinogen appears to be involved in
the regulation of fat mass through a combination of de-
ANG II plays a role in sympathetic nervous system- creased lipogenesis and increased locomotor activity that
mediated thermogenesis. Cold exposure resulted in an may be centrally mediated (439). ANG II has been shown
increase in interscapular fat ANG II content, without con- to be able to induce leptin expression in adipocytes (344),
comitant changes in plasma components of the RAS, and and Cassis et al. (82) suggested that in contrast to sys-

led to an ANG II-mediated presynaptic facilitation of temic ANG II, only locally produced ANG II is able to
evoked norepinephrine overflow from rat interscapular elevate plasma leptin levels, since systemic ANG II also
fat during cold exposure that can be diminished by losar- leads to sympathetic activation, which would diminish the
tan (80). Cold exposure induced an increase of ANG II in effect of ANG II.
brown adipose tissue without detectable changes in
plasma components of the RAS and mediated facilitation
of sympathetic neurotransmission (80, 81). III. PRENATAL DEVELOPMENT
Treatment of cultured human preadipocytes with
ANG II resulted in an AT1 receptor-mediated increase of Local ANG formation and tissue-specific effects of
expression of the mRNA for cell cycle regulatory protein ANG peptides on growth and differentiation are thought
cyclin D1 (120). The role of ANG II in adipose cell matu- to be extremely important for embryonic and fetal devel-
ration and growth was also supported by a study that opment. There appears to be a close interaction between
showed the differences in angiotensinogen mRNA and plasma and tissue RAS in this situation.
protein content between young and adult rats (258). An-
giotensinogen mRNA (protein) was approximately two- 1. Renin
fold (3-fold) higher in adipocytes of young (8 wk) rats Newborn rat plasma renin activity and plasma renin
compared with old ones (26 wk). Interestingly, Brink et al. concentration are higher than adult levels (551, 755). In
(60) have found that ANG II infusion to rats caused many the rabbit fetus, plasma renin activity shows very low
systemic changes like decreasing skeletal muscle mass or values but increases rapidly during the last 4 days of
increasing left ventricular weight, but fat tissue was un- gestation and reaches a maximal level in the early post-
changed. natal period. Siegel and Fisher (651) have shown that
Safonova et al. (588) showed that angiotensinogen furosemide-induced plasma renin activity was for the first
gene expression in adipocytes is activated by fatty acid time inducible at 106 days of gestation and increased with
levels in a dose-dependent manner. Jones et al. (327) the gestational age in the fetal lamb and that the fetal
showed that ANG II significantly increased triglyceride lamb plasma aldosterone level did not increase in re-
content and the activities of two key lipogenic enzymes sponse to endogenous renin stimulation.
(fatty acid synthase and glycerol-3-phosphate dehydroge-
nase) in 3T3-L1 and human adipose cells. Interestingly,
2. ACE
this effect was mediated by the AT2 receptor, in contrast
to other publications that predominantly or exclusively Rat somatic ACE is first identifiable at 18 days of
detected AT1 receptors (68, 121, 327). Body weight corre- gestation and increases thereafter until 2– 6 wk postpar-
lated positively with adipose angiotensinogen mRNA ex- tum (656, 753, 754). In addition, in the human fetal lung,
pression in humans (226, 732). Kouyama et al. (360) have ACE activity increased with gestation and reaches its
shown that mice lacking AT1A receptor have higher en- mature activity earlier than those in the rat (656). Plasma
ergy expenditure and thus show attenuation of diet-in- ACE correlated with gestational age of fetal lambs and
duced weight gain and adiposity. A role of angiotensino- was associated with prepartum increases in plasma cor-
gen, derived from adipose tissue, in blood pressure regu- tisol and blood pressure; by 2 wk of postnatal age, plasma
lation and adipose tissue volume has been postulated ACE had decreased to the value seen in nonpregnant
(438). Using angiotensinogen-deficient mice with reduced adult ewes. The maternal plasma ACE was similar at all

gestational stages (213). Also, in fetal rabbit, an increase expression was highest in the human metanephros at 8 –9
of pulmonary ACE activity was detected from 22 days of wk gestational age. It could be detected in undifferenti-
gestation until term (672). ated mesenchyme, surrounding tubules and immature glo-
meruli. The AT2 receptor mRNA signal in the human
3. Angiotensinogen metanephros declined after 20 wk of gestation but re-
mained detectable until birth. Also, both mRNA and pro-
The major portion of angiotensinogen mRNA in the
tein for AT1 and AT2 receptors were present in the ovine
embryo is most likely derived from the fetal liver, and the
fetal metanephroi (69).
level in the whole rat embryo was increasing by day 13
A recent study (504) has indicated a positive-feed-
and reached a plateau by day 17 (380). Furthermore, the
back mechanism for renin generation in cultured devel-
authors suggested that the poly(A) tract of rat embryonic
oping rat metanephron. Renin mRNA was localized to
angiotensinogen mRNA may be longer than that of adult
developing tubules and uretral branches and glomeruli in
liver angiotensinogen mRNA.
the cultured explants. Also, both ANG II receptors and
4. Angiotensin receptors ANG II were detected in the rat cultured metanephroi.
After ANG II treatment, the authors detected an increase
The high abundance of AT2 receptors in fetal tissue in renin activity that was prevented by AT1 blockade,
and in vitro studies suggesting the involvement of AT2

whereas AT2 antagonism had no effect.
receptors in mediating programmed cell death (797) and Maric et al. (434) have detected AT1 and AT2 receptor
cell differentiation (680, 681) have lead to the hypothesis binding sites by radiolabeled binding assay and AT1 and
that ANG II, acting via the AT2 receptor, is involved in AT2 receptor mRNA (RT-PCR) in isolated embryonic
aspects of organogenesis. renomedullary interstitial cells from embryonic rat kid-
neys. The authors have demonstrated that ANG II acts as
5. Kidney a potent mitogen to those cells in a time- and dose-
A) MESONEPHROS. Renin is expressed very strongly from dependent manner. This effect could be abolished with
stage 13 in capillaries within glomeruli as well as in the losartan but not with PD123319, suggesting that the mito-
wall of arteries in the interstitium and in the arterioles up genic effect of ANG II is mediated through the AT1 recep-
to the aorta of the human embryonic mesonephros (630). tor. ANG II was also able to inhibit growth induced by
ACE protein can be detected by immunohistochemistry at basic fibroblast growth factor mediated by the AT2 recep-
stage 14 in the apical membrane of the human mesoneph- tor (681). Gimonet et al. (228) have shown that both ANG
ric tubule cells. Angiotensinogen mRNA was detected by II receptor subtypes are expressed early during nephro-
stage 12–13 in the proximal portion of the primitive tu- genesis in fetal lamb but displayed specific spatial and
bules of the human mesonephros. The AT1 receptor temporal distribution during gestation. The level of AT2
mRNA was detected in human mesonephric glomeruli, expression followed closely glomeruli proliferation rate
probably in mesangial cells, beginning at stage 12, and the and disappeared after nephrogenesis completion. Also, in
AT2 receptor mRNA was the component to be expressed the differentiated epithelial cells of macula densa, AT2
first (stage 11) and was confined to the undifferentiated mRNA was detected. AT1 receptor was predominant in
mesenchyme of the human mesonephros surrounding the mesangial cells of mature glomeruli but was also detected
preliminary tubules and glomeruli. In addition, both the in cells invading the inferior cleft of S-shaped bodies and
mRNA and protein for AT1 and AT2 receptors were in medullar cells between tubules.
present in the ovine fetal mesonephri (69). Mice lacking AT1B receptor are healthy, without an
B) METANEPHROS. The distribution of renin mRNA in hu- abnormal phenotype. In contrast, Agtr1a⫺/⫺ Agtr1b⫺/⫺
man metanephros appeared slightly different from that in mice have diminished growth, vascular thickening within
the mesonephros as it had become confined to the juxta- the kidney, and atrophy of the inner renal medulla (70).
glomerular apparatus at the vascular pole of the glomer- The complete AT1 receptor knockout mice have no sys-
ulus and to dispersed cells of arteries located next to temic response to infusions of ANG II, and the blood
glomeruli. In human metanephros, ACE activity was de- pressure is reduced substantially. Interestingly, after ad-
tected in proximal convoluted tubules and collecting ministration of an ACE inhibitor, their blood pressure
ducts in increasing amounts until birth (630). In the hu- increases paradoxically. This could be a result of inter-
man metanephros, angiotensinogen mRNA showed only ruption of AT2 receptor signaling.
weak labeling macroscopically and was expressed in Miyazaki et al. (449) have shown that AT1 receptor
proximal tubules from 8 wk of and throughout gestation. knockout mice do not develop renal pelvis or ureteral
Hybridization signal for AT1 receptor mRNA was ob- peristaltic movement. Comparing the Agtr1⫺/⫺ neonatal
served in human metanephros glomeruli and in proximal mice with complete unilateral ureteral ligated wild-type
tubular epithelium. Juxtaglomerular cells expressed AT1 neonates, the structural anomalies were qualitatively in-
mRNA as soon as they differentiated. AT2 receptor mRNA distinguishable between the Agtr1⫺/⫺ neonatal mice

without surgical obstruction versus the wild-type mice production in the midgestation ovine fetus. However,
with complete unilateral ureteral ligation. In both kid- plasma aldosterone could be stimulated by ANG II in the
neys, the calyx was enlarged and the papilla was atrophic presence of a specific AT2 receptor blocker treatment,
(449). Moreover, tubulointerstitial inflammation, e.g., suggesting that this may be mediated by AT2 receptors.
macrophage infiltration and fibrosis, shows the same pat- The AT2 receptor shows high density in the medulla
tern. Thus the authors suggested that the abnormal kid- of the adult adrenal gland of rats and rabbits but is
ney structure that develops in neonates during ANG inhi- virtually absent from the medulla of the human and bo-
bition is attributed largely to functional obstruction of the vine adrenal glands.
urinary tract caused by the defective development of
peristaltic machinery (449). Interestingly, the irreversible 7. Heart
renal abnormalities that are induced by ANG II type 1
Renin mRNA could be detected in a few cells of the
receptor blockade or ACE inhibition were attenuated by
human embryonic heart starting expression at stage 12
simultaneous infusion of insulin-like growth factor I to
and became more abundant during the course of gesta-
rats at perinatal days 3–13 (499).
tion, although the positive cells always remained isolated
and preferentially located in the inner parts of the myo-
6. Adrenal gland cardium (630). ACE activity was first detected at stage 14

in the inner layer of the human embryonic heart wall by
Renin was detected in the cortex of adrenal gland of
these authors. AT1 receptor mRNA was diffusely distrib-
mouse fetus, appearing as small patchy or granular reac-
uted over the human embryonic heart muscle, whereas
tion products in the perikaryon of a few cells. Later in the
AT2 receptor mRNA was detected earlier, expressed at a
gestation, numerous tiny granules were found just below
higher level, and located in the innermost layers of the
the cell membrane (358). The AT1 receptor mRNA could
myocardium. By quantitative autoradiography, ANG II re-
be detected in the neocortex of human adrenal gland at 8
ceptors were first detected in the rat myocardium on
wk and throughout the gestation (neocortex differenti-
embryonic day 14 and reached a maximum density within
ates into the zona glomerulosa, fasciculata, and reticularis
the first postnatal week (294).
around the time of birth), whereas AT2 receptor mRNA is
Both ANG II receptor subtypes are involved in the
expressed earlier (5– 6 wk) in a mass of condensed cells
regulation of type I and III collagen expression and struc-
above the developing kidney, namely, the future adrenal
tural protein accumulation in the developing rat heart,
fetal zone (630). The majority of ANG binding sites in
since type I collagen expression in cardiac tissue was
primary cultures of both human fetal zone and neocortex
reduced and type III collagen mRNA expression increased
cells were of the type 1 subtype (564). However, Breault
in both losartan and PD123319-treated rats (371).
et al. (58) detected by autoradiographic studies that ANG
A moderate density of binding to ACE was first de-
II receptors in the human fetal adrenals are mainly of the
tected in the rat cardiac vasculature and heart valves on
type 2, suggesting that culture conditions increase AT1
embryonic day 19, whereas ACE was first detected in the
receptor expression.
rat myocardium on the day of birth, with the density of
In contrast to observations in rat fetus, the adrenal
binding to ACE increasing during development (294).
medulla of the human fetus does not express AT2 receptor
More recently, a pivotal role of ACE2 for normal heart
mRNA (630). In the ovine fetal adrenal gland, Wintour et
development and function has been demonstrated for the
al. (779) could detect both mRNA and protein of the AT1
ACE2 homolog ACER in Drosophila (119) and for ACE2
receptor in the zona glomerulosa and fasciculata of the
in mice (119).
cortex, but not in the medulla by 60 days of gestation. The
mRNA of AT2 receptor was present in the same location
8. Vasculature
(and absent in the medulla) from 40 to 130 days and
declined to extremely low levels after 140 days (term is During rat aortic development, AT1 expression was
145–150 days). The authors showed that the application of detected on gestational day 14, increased until embryonic
ANG II caused a significant downregulation of the AT1 day 16, after which levels were similar throughout post-
receptor mRNA expression, and the AT2 mRNA levels natal development; conversely, AT2 mRNA first appeared
remained unchanged. The adult ovine adrenal expresses at day 16, reached maximal levels between day 19 and
only AT1 receptor mRNA (zona glomerulosa and to a neonatal day 1, and decreased thereafter (295). DNA
lesser extent in the zona fasciculata, but never in the synthesis rates decreased with aortic development, and
medulla) (779). AT1 receptor antagonism accelerates this developmen-
Moritz et al. (464) showed a functional antagonistic tally regulated decrease in DNA synthesis, whereas AT2
effect of the ANG II receptors by aldosterone secretion by receptor antagonism blunted this decrease. Yamada et al.
the midgestation ovine fetus. In this study, a short-term (795) have also demonstrated that the expression of this
infusion of ACTH but not ANG II stimulated aldosterone receptor mediates decline in vascular DNA synthesis that

occurs at this stage of vascular development. The AT2 thelium at day 13 of gestation; in the subthalamic and
receptor promotes also vascular differentiation and con- hypoglossus nuclei at day 15; in the pedunculopontine
tributes to vasculogenesis. These authors could demon- nucleus, cerebellum, motor facial nucleus, and the infe-
strate that AT2 knockout mice show lower mRNA levels rior olivary complex at day 17; in the thalamus, bed
for calponin in the aorta as the wild-type mouse aorta nucleus of the supraoptic decussation, interstitial nucleus
(795). Calponin is expressed in the late stage of vascular of Cajal, nuclei of lateral lemniscus, locus ceruleus, and
smooth muscle cell differentiation and correlates with supragenual nucleus at day 19; and in the lateral septal
expression of the AT2 receptor. The authors have also and medial amygdaloid nuclei, medial geniculate body,
demonstrated that the protein levels of calponin and high- and the superior colliculus at day 21. The substantia nigra
molecular-weight caldesmon were lower in the aorta of and many telencephalic and medullary nuclei did not
AT2 receptor knockout mice at 2 and 4 wk after birth. show AT2 mRNA expression; however, AT2 is expressed
after birth in these regions (507). In nuclei involved in
9. Liver motor function and sensory integration, the AT2 mRNA
expression is high and persists until brain maturity (507).
In the human embryonic liver, hepatocytes show an
By autoradiography study, Tsutsumi and co-workers (721,
extremely high level of angiotensinogen mRNA during
723) have detected AT1 receptor binding sites in the nu-
formation from the foregut epithelium (630). On days

cleus of the solitary tract, subfornical organ, paraven-
14 –15, the rat embryonic liver had reached adult mor-
phology, and during this period, angiotensinogen mRNA tricular nucleus, and choroid plexus of fetal rat brain; AT2
levels increased exponentially (380). Besides angio- binding sites were detected in the inferior olive, paratri-
tensinogen, AT1 receptor mRNA was also expressed in geminal and hypoglossal nuclei, in meninges, and ce-
the human embryonic liver, but no expression of renin, phalic soft tissues including cerebral arteries and high
ACE, and AT2 receptor could be detected in the liver at ACE concentrations in choroid plexus, subfornical organ,
any stage of development. posterior pituitary, and cerebral arteries. Primary cultures
of astrocytes obtained from fetal rats showed ANG II
10. Brain binding sites belonging only to the AT1 subtype (56).
Distinct cells (probably from neural crest) around
Immunostaining for ACE was observed in the devel- the neural groove and somites showed hybridization sig-
oping nervous system and dermomyotome (630). Low nal for AT2 receptor. During later development, the sym-
levels of angiotensinogen mRNA were detected in the rat pathetic ganglion chain showed also a strong hybridiza-
embryo head from days 17 to 19 (380). However, others tion signal for the AT2 receptor. Furthermore, all organs
have shown that angiotensinogen mRNA was more abun- that contain components of neural crest origin were la-
dant in brain than in the liver in the early gestational life beled at stages 14 –16 (630).
of rat embryo (soon after birth, brain angiotensinogen
mRNA levels increased to a concentration 3-fold above 11. Extraembryonic fetal tissues
fetal levels and liver angiotensinogen mRNA abundance
increased 30-fold within 12 h of birth) (333). By immuno- A) RENIN. Renin immunoreactivity was found in the
staining, angiotensinogen was first observed on rat em- human decidua and placenta (447). Renin mRNA and ACE
bryonic day 18 in the choroid plexus and ependymal cells immunoreactivity were detected in the chorion, renin
lining the third ventricle (474). During early postnatal mRNA in the cells of the chorionic mesenchyme, and ACE
development, a rapid progression of angiotensinogen in the epithelium of the chorion (630). The presence of
staining appears in the astrocytes in the paraventricular renin in human trophoblastic and amnioblastic cells was
nucleus, medial preoptic area, and ventromedial and ar- detected via immunostaining by Poisner et al. (552, 553).
cuate hypothalamic nuclei. Sood et al. (663) have de- Paul et al. (532) demonstrated renin mRNA in the pla-
tected angiotensinogen immunoreactivity in the hindbrain centa. Renin mRNA was detectable in the human chorio-
and the spinal cord of rat fetuses. This immunoreactivity decidua, whereas no renin mRNA was detected in the
was associated with an active cell differentiation and cell intertwin chorion, chorionic basal plate, placental villae,
growth. ANG II immunoreactivity was found in cells cul- or amnion (299, 641). In the human choriodecidua, renin
tured from fetal rat brain of 20-day-old fetuses (770). mRNA was localized in macrophages (319) and smooth
These cells have been identified as neurons on the basis of muscle cells of veins and spiral arteries (460). Finally, the
morphological criteria. The AT1 receptor could be visual- presence of renin protein was shown by Kalenga et al.
ized in parts of the developing brain (630). (332). More recently, the newly high mRNA levels of the
Brain AT2 mRNA was detected in many brain nuclei newly identified prorenin/renin receptor were detected in
in the early stage of rat prenatal development, and there the placenta (488, 490).
was strong but transient AT2 mRNA expression in certain B) ACE. ACE mRNA and activity in human or rat pla-
structures including the lateral hypothalamic neuroepi- centa were shown by several studies (332, 656, 793).

Human fetopathies were seen when ACE inhibitors of the plasma RAS as can be concluded from experiments
were given around the 26th week of gestation. The major where nephrectomy (downregulating the formation of
adverse effects in babies include the following: oligohy- ANG II in the plasma) led to upregulation or no changes
dramnios, renal tubular dysgenesis, neonatal anuria, cal- of locally formed ANG II such as in adrenal gland or brain.
varial and pulmonary hypoplasia, mild to severe intrauter- In other organ systems, there appears to be close cross-
ine growth retardation, persistent patent ductus arterio- talk between the local and plasma RAS. Components of
sus, and fetal or neonatal death (70). the system such as renin or angiotensinogen in the heart,
C) ANGIOTENSINOGEN, ANG I, AND ANG II. Angiotensinogen for example, may be taken up from the circulation and
mRNA was undetectable in any of the placental tissues and stored locally to be available for local ANG synthesis and
hydatidiform moles using Northern blotting (299). Angio- action. In some cases, specific independent actions have
tensinogen mRNA was demonstrated in human placenta and been assigned to RAS components, for example, in the
decidua using more sensitive detection methods (459, 532), testis where a role in fertility and sperm motility is dis-
and Lenz et al. (389, 390) found high angiotensinogen con- cussed.
centrations in homogenates of the human placenta. Further- If there is a common denominator for the physiolog-
more, angiotensinogen was detected in the human placenta ical role of these local systems, it is the maintenance of a
and decidua by immunohistochemistry (447). The human balance or homeostasis at the tissue level between oppos-

choriodecidua was found to secrete ANG I in vitro (122). ing effects mediated by the system such as growth pro-
The human yolk sac expressed angiotensinogen mRNA in motion and inhibition, for example, in the heart and blood
the inner endodermal layer and the AT1 receptor in the outer vessels. The dual actions of ANG II on its receptors can be
mesodermal layer. Lee et al. (380) suggested a role for considered as a basis for this balance. In addition, the
angiotensinogen in yolk sac function, since angiotensinogen possibility of alternative pathways including the use of
mRNA was detected in the yolk sac placenta. ANG II has the different substrates such as AC-SDKP for ACE, different
ability to promote angiogenesis in a variety of tissues. This receptors such as AT4, and different processing products
property could be important for the placenta and/or fetus such as ANG-(1O7) can be responsible for mediating the
due to the significant vascularization that takes place during regulatory and counterregulatory effects. If this balance is
early pregnancy. Amniotic fluid of humans contains active disturbed, for example, by overexpression of RAS com-
and inactive renin, angiotensinogen, and ANG I and II (659). ponents or inhibition of others, the RAS becomes a me-
Explants of human chorion-decidua and amnion generate diator of pathophysiological stimuli. In these regulatory
ANG I when cultured in serum-free medium (122). processes, the plasma RAS takes up the role of an acute
D) ANGIOTENSIN RECEPTORS. The ANG II receptors in the “response unit,” whereas tissue-based ANG II formation is
human placenta are predominantly AT1 receptors (350, 409), more linked to subacute and chronic modulation. The
but a small population of non-AT1/non-AT2 binding sites was concept of local or tissue-based RAS, therefore, should
also identified. ANG II receptors were also demonstrated in not be considered as an opposing or alternative but rather
placentae and fetal membranes of the pig (498), sheep (809), as a complimentary or integrated functional concept of
and cow (605). In the human placenta, both AT1 receptor ANG formation and function. There is clearly no basis for
mRNA protein increased from the first trimester and any controversy.
reached the highest levels at term (545). In mice placenta
ACKNOWLEDGMENTS
only was AT1A receptor mRNA detectable (68).
E) ANGIOTENSINASES. The placenta is rich in angiotensi- We thank Doris Webb and Jessie Webb for excellent sec-
nases capable of ANG II degradation (321, 484). An in- retarial and technical support.
creased expression of villous trophoblastic angiotensi- Address for reprint requests and other correspondence: R.
Kreutz, Institute of Clinical Pharmacology and Toxicology, Cam-
nase A, suggesting an increased ANG II degradation, was
pus Benjamin Franklin, Charité-University Medicine Berlin, Hin-
recently demonstrated to relate to an increased frequency denburgdamm 30, 12200 Berlin, Germany (e-mail: reinhold.
of preeclampsia (484). However, the role of RAS in the kreutz@charite.de).
development of preeclampsia is still not clear. An in-
creased level of renin expression and increased sensitiv- GRANTS
ity on AT1 receptors as well as antibodies against AT1 This work was supported by Nationales Genomforschung-
receptors point toward an involvement during this patho- snetz Grant KGCV1, 01GS0416.
logical state (638).
REFERENCES
IV. SUMMARY 1. AbdAlla S, Lother H, Abdel-tawab AM, and Quitterer U. The
angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol
Chem 276: 39721–39726, 2001.
The local RAS exerts diverse actions in many organs. 2. Abel KJ and Gross KW. Close physical linkage of the murine
In some tissues they appear to be regulated independently Ren-1 and Ren-2 loci. Nucleic Acids Res 16: 2111–2126, 1988.

3. Abiko M, Rodgers KE, Campeau JD, Nakamura RM, and Diz- hypertension. Am J Physiol Heart Circ Physiol 267: H1777–H1784,
erega GS. Alterations of angiotensin II receptor levels in sutured 1994.
wounds in rat skin. J Invest Surg 9: 447– 453, 1996. 23. Aschoff JM, Lazarus D, Fanburg BL, and Lanzillo JJ. Relative
4. Ackermann A, Fernandez-Alfonso M, Sanchez de Rojas R, quantification of angiotensin-converting enzyme mRNA in human
Ortega T, Paul M, and Gonzalez C. Modulation of angiotensin- smooth muscle cells, monocytes, and lymphocytes by the polymer-
converting enzyme by nitric oxide. Br J Pharmacol 124: 291–298, ase chain reaction. Anal Biochem 219: 218 –223, 1994.
1998. 24. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Mee-
5. Admiraal PJ, van Kesteren CA, Danser AH, Derkx FH, Sluiter han WP, Tuan TL, and Hsueh WA. Osteopontin is produced by
W, and Schalekamp MA. Uptake and proteolytic activation of rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis
prorenin by cultured human endothelial cells. J Hypertens 17: and collagen gel contraction. J Clin Invest 98: 2218 –2227, 1996.
621– 629, 1999. 25. Azizi M, Ezan E, Nicolet L, Grognet JM, and Menard J. High
6. Aguilera G, Kiss A, and Luo X. Increased expression of type 1 plasma level of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: a new
angiotensin II receptors in the hypothalamic paraventricular nu- marker of chronic angiotensin-converting enzyme inhibition. Hy-
cleus following stress and glucocorticoid administration. J Neu- pertension 30: 1015–1019, 1997.
roendocrinol 7: 775–783, 1995. 26. Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet
7. Aguilera G, Millan MA, and Harwood JP. Angiotensin II recep- JM, Lenfant M, Corvol P, and Menard J. Acute angiotensin-
tors in the gonads. Am J Hypertens 2: 395– 402, 1989. converting enzyme inhibition increases the plasma level of the
8. Ahmed A, Li XF, Shams M, Gregory J, Rollason T, Barnes NM, natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline.
and Newton JR. Localization of the angiotensin II and its receptor J Clin Invest 97: 839 – 844, 1996.
subtype expression in human endometrium and identification of a 27. Bader M, Paul M, Fernandez-Alfonso M, Kaling M, and Gan-
novel high-affinity angiotensin II binding site. J Clin Invest 96: ten D. Molecular biology and biochemistry of the renin-angiotensin

848 – 857, 1995. system. In: Textbook of Hypertension, edited by Swales JD. Oxford,
9. Alexander RW and Griendling KK. Signal transduction in vas- UK: Blackwell, 1994, p. 214 –232.
cular smooth muscle. J Hypertens Suppl 14: S51–S54, 1996. 28. Bader M, Peters J, Baltatu O, Muller DN, Luft FC, and Ganten
10. Allen AM, Chai SY, Sexton PM, Lewis SJ, Verberne AJM, D. Tissue renin-angiotensin systems: new insights from experimen-
Jarrott B, Louis WJ, Clevers J, McKinley MJ, Paxinos G, and tal animal models in hypertension research. J Mol Med 79: 76 –102,
Mendelsohn FAO. Angiotensin II receptors and angiotensin con- 2001.
verting enzyme in the medulla oblongata. Hypertension 9: 197–205, 29. Baker KM, Chernin MI, Wixson SK, and Aceto JF. Renin-
1987. angiotensin system involvement in pressure-overload cardiac hy-
11. Allen AM, Lewis SJ, Verberne AJ, and Mendelsohn FAO. pertrophy in rats. Am J Physiol Heart Circ Physiol 259: H324 –
Angiotensin receptors and the vagal system. Clin Exp Hypertens H332, 1990.
10: 1239 –1249, 1988.
30. Balcells E, Meng QC, Johnson WH Jr, Oparil S, and Dell’Italia
12. Allen AM, McKinley MJ, Oldfield BJ, Dampney RA, and Men-
LJ. Angiotensin II formation from ACE and chymase in human and
delsohn FA. Angiotensin II receptor binding and the baroreflex
animal hearts: methods and species considerations. Am J Physiol
pathway. Clin Exp Hypertens 10: 1, 1988.
Heart Circ Physiol 273: H1769 –H1774, 1997.
13. Allen AM, Moeller I, Jenkins TA, Zhuo J, Aldred GP, Chai SY,
31. Baltatu O and Bader M. Brain renin-angiotensin system. Lessons
and Mendelsohn FA. Angiotensin receptors in the nervous sys-
from functional genomics. Neuroendocrinology 78: 253–259, 2003.
tem. Brain Res Bull 47: 17–28, 1998.
32. Baltatu O, Cayla C, Iliescu R, Andreev D, and Bader M. Abo-
14. Allen AM, Yamada H, and Mendelsohn FA. In vitro autoradio-
lition of end-organ damage by antiandrogen treatment in female
graphic localization of binding to angiotensin receptors in the rat
hypertensive transgenic rats. Hypertension 41: 830 – 833, 2003.
heart. Int J Cardiol 28: 25–33, 1990.
15. Ambroz C, Clark AJL, and Catt KJ. The mas oncogene enhances 33. Baltatu O, Lippoldt A, Hansson A, Ganten D, and Bader M.
angiotensin-induced [Ca2⫹]i responses in cells with pre-existing Local renin-angiotensin system in the pineal gland. Brain Res 54:
angiotensin II receptors. Biochim Biophys Acta 1133: 107–111, 237–242, 1998.
1991. 34. Baltatu O, Nishimura H, Hoffmann S, Stoltenburg G, Haulica
16. Aneman A, Pettersson A, Eisenhofer G, Friberg P, Holm M, ID, Lippoldt A, Ganten D, and Urata H. High levels of human
von Bothmer C, and Fandriks L. Sympathetic and renin-angio- chymase expression in the pineal and pituitary glands. Brain Res
tensin activation during graded hypovolemia in pigs: impact on 752: 269 –278, 1997.
mesenteric perfusion and duodenal mucosal function. Shock 8: 35. Baltatu O, Silva JA, Ganten D, and Bader M. The brain renin-
378 –384, 1997. angiotensin system modulates angiotensin II-induced hypertension
17. Aneman A, Svensson M, Broome M, Biber B, Petterson A, and and cardiac hypertrophy. Hypertension 35: 409 – 412, 2000.
Fandriks L. Specific angiotensin II receptor blockage improves 36. Barth SW and Gerstberger R. Differential regulation of angio-
intestinal perfusion during graded hypovolemia in pigs. Crit Care tensinogen and AT1A receptor mRNA within the rat subfornical
Med 28: 818 – 823, 2000. organ during dehydration. Brain Res 64: 151–164, 1999.
18. Antunes VR, Camargo GM, Saad R, Saad WA, Luiz AC, and 37. Bascands JL, Girolami JP, Troly M, Escargueil-Blanc I, Naz-
Camargo LA. Role of angiotensin II and vasopressin receptors zal D, Salvayre R, and Blaes N. Angiotensin II induces pheno-
within the supraoptic nucleus in water and sodium intake induced type-dependent apoptosis in vascular smooth muscle cells. Hyper-
by the injection of angiotensin II into the medial septal area. Braz tension 38: 1294 –1299, 2001.
J Med Biol Res 31: 1597–1600, 1998. 38. Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jean-
19. Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, and Kajstura neret L, van Kats JP, Saxena PR, and Danser AH. Angiotensin
J. Apoptosis and myocardial infarction. Basic Res Cardiol 93 II type 2 receptor-mediated vasodilation in human coronary micro-
Suppl 3: 8 –12, 1998. arteries. Circulation 109: 2296 –2301, 2004.
20. Arakawa K and Urata H. Hypothesis regarding the pathophysio- 39. Batenburg WW, Tom B, Schuijt MP, and Danser AH. Angioten-
logical role of alternative pathways of angiotensin II formation in sin II type 2 receptor-mediated vasodilation. Focus on bradykinin,
atherosclerosis. Hypertension 36: 638 – 641, 2000. NO and endothelium-derived hyperpolarizing factor(s). Vasc Phar-
21. Armando I, Jezova M, Juorio AV, Terron JA, Falcon-Neri A, macol 42: 109 –118, 2005.
Semino-Mora C, Imboden H, and Saavedra JM. Estrogen up- 40. Baxter JD, James MN, Chu WN, Duncan K, Haidar MA, Carilli
regulates renal angiotensin II AT(2) receptors. Am J Physiol Renal CT, and Reudelhuber TL. The molecular biology of human renin
Physiol 283: F934 –F943, 2002. and its gene. Yale J Biol Med 62: 493–501, 1989.
22. Arnal JF, Battle T, Rasetti C, Challah M, Costerousse O, 41. Belcheva I, Chobanova M, and Georgiev V. Differential behav-
Vicaut E, Michel JB, and henc-Gelas F. ACE in three tunicae of ioral effects of angiotensin II microinjected unilaterally into the
rat aorta: expression in smooth muscle and effect of renovascular CA1 hippocampal area. Regul Pept 74: 67–71, 1998.

42. Belcheva I, Georgiev V, Chobanova M, and Hadjiivanova C. 63. Brunswig-Spickenheier B and Mukhopadhyay AK. Inhibitory
Behavioral effects of angiotensin II microinjected into CA1 hip- effects of a tumor-promoting phorbol ester on luteinizing hormone-
pocampal area. Neuropeptides 31: 60 – 64, 1997. stimulated renin and prorenin production by cultured bovine theca
43. Belcheva I, Ternianov A, and Georgiev V. Lateralized learning cells. Endocrinology 127: 2157–2165, 1990.
and memory effects of angiotensin II microinjected into the rat CA1 64. Brunswig-Spickenheier B and Mukhopadhyay AK. Character-
hippocampal area. Peptides 21: 407– 411, 2000. ization of angiotensin-II receptor subtype on bovine thecal cells
44. Benarroch EE and Schmeichel AM. Immunohistochemical local- and its regulation by luteinizing hormone. Endocrinology 131:
ization of the angiotensin II type 1 receptor in human hypothalamus 1445–1452, 1992.
and brainstem. Brain Res 812: 292–296, 1998. 65. Bunnemann B, Fuxe K, Metzger R, Bjelke B, and Ganten D.
45. Berg T, Sulner J, Lai CY, and Soffer RL. Immunohistochemical The semi-quantitative distribution and cellular localization of an-
localization of two angiotensin I-converting isoenzymes in the re- giotensinogen mRNA in the rat brain. J Chem Neuroanat 5: 245–
productive tract of the male rabbit. J Histochem Cytochem 34: 262, 1992.
753–760, 1986. 66. Burns GA, nn-Marie T, Jodie H, and Harding JW. AT4 receptor
46. Bergaya S, Hilgers RH, Meneton P, Dong Y, Bloch-Faure M, binding in the developing rabbit. Anat Rec 281: 1276 –1285, 2004.
Inagami T, henc-Gelas F, Levy BI, and Boulanger CM. Flow- 67. Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS,
dependent dilation mediated by endogenous kinins requires angio- Lu S, Tikellis C, Grant SL, Lew RA, Smith AI, Cooper ME, and
tensin AT2 receptors. Circ Res 94: 1623–1629, 2004. Johnston CI. Myocardial infarction increases ACE2 expression in
47. Berger S, Bleich M, Schmid W, Greger R, and Schutz G. Min- rat and humans. Eur Heart J 26: 369 –375, 2005.
eralocorticoid receptor knockout mice: lessons on Na⫹ metabo- 68. Burson JM, Aguilera G, Gross KW, and Sigmund CD. Differ-
lism. Kidney Int 57: 1295–1298, 2000. ential expression of angiotensin receptor 1A and 1B in mouse.
48. Bernstein KE, Martin BM, Edwards AS, and Bernstein EA. Am J Physiol Endocrinol Metab 267: E260 –E267, 1994.
Mouse angiotensin-converting enzyme is a protein composed of 69. Butkus A, Albiston A, Alcorn D, Giles M, McCausland J,

two homologous domains. J Biol Chem 264: 11945–11951, 1989. Moritz K, Zhuo J, and Wintour EM. Ontogeny of angiotensin II
49. Bhaskar RM, O’Dorisio TM, Cataland S, George JM, and Gag- receptors, types 1 and 2, in ovine mesonephros and metanephros.
inella TS. Angiotensin II and norepinephrine antagonize the secre- Kidney Int 52: 628 – 636, 1997.
tory effect of VIP in rat ileum and colon. Peptides 5: 291–294, 1984. 70. Buttar HS. An overview of the influence of ACE inhibitors on
50. Bickerton R and Buckley JP. Evidence for a central mechanism fetal-placental circulation and perinatal development. Mol Cell Bio-
of angiotensin induced hypertension. Proc Soc Exp Biol Med 106: chem 176: 61–71, 1997.
834 – 837, 1961. 71. Cai H, Griendling KK, and Harrison DG. The vascular NAD(P)H
51. Blair-West JR, Denton DA, McKinley MJ, and Weisinger RS. oxidases as therapeutic targets in cardiovascular diseases. Trends
Central infusion of the AT1 receptor antagonist losartan inhibits Pharmacol Sci 24: 471– 478, 2003.
thirst but not sodium appetite in cattle. Am J Physiol Regul Integr 72. Campbell DJ, Bouhnik J, Menard J, and Corvol P. Identity of
Comp Physiol 272: R1940 –R1945, 1997. angiotensinogen precursors in rat brain and liver. Nature 308:
52. Bode W, Fernandez-Catalan C, Grams F, Gomis-Ruth FX, 206 –208, 1984.
Nagase H, Tschesche H, and Maskos K. Insights into MMP-TIMP 73. Campbell DJ and Habener JF. Cellular localization of angio-
interactions. Ann NY Acad Sci 878: 73–91, 1999. tensinogen gene expression in brown and adipose tissue and mes-
53. Bokil HS and Porter JP. Brain angiotensin type 1 receptor ex- entery: quantification of messenger ribonucleic acid abundance
pression and function in the Zucker obese rat. Neurosci Lett 281: using hybridization in situ. Endocrinology 121: 1616 –1626, 1987.
139 –142, 2000. 74. Campbell DJ and Habener JF. Angiotensinogen gene is ex-
54. Bonnet F, Cooper ME, Carey RM, Casley D, and Cao Z. Vas- pressed and differentially regulated in multiple tissues of the rat.
cular expression of angiotensin type 2 receptor in the adult rat: J Clin Invest 78: 31–39, 1986.
influence of angiotensin II infusion. J Hypertens 19: 1075–1081, 75. Campbell-Boswell M and Robertson AL Jr. Effects of angioten-
2001. sin II and vasopressin on human smooth muscle cells in vitro. Exp
55. Booz G and Baker K. Role of the type 1 and type 2 angiotensin Mol Pathol 35: 265–276, 1981.
receptors in angiotensin II-induced cardiomyocyte hypertrophy. 76. Capponi AM. The control by angiotensin II of cholesterol supply
Hypertension 28: 635– 640, 2002. for aldosterone biosynthesis. Mol Cell Endocrinol 217: 113–118,
56. Bottari SP, Obermuller N, Bogdal Y, Zahs KR, and Deschepper 2004.
CF. Characterization and distribution of angiotensin II binding 77. Carey RM, Jin XH, and Siragy HM. Role of the angiotensin AT2
sites in fetal and neonatal astrocytes from different rat brain re- receptor in blood pressure regulation and therapeutic implications.
gions. Brain Res 585: 372–376, 1992. Am J Hypertens 14: 98S–102S, 2001.
57. Brar HS, Do YS, Tam HB, Valenzuela GJ, Murray RD, Longo 78. Carey RM, Levens NR, and Peach MJ. Regulation of intestinal
LD, Yonekura ML, and Hsueh WA. Uteroplacental unit as a fluid transport by angiotensin II: mechanisms and physiological
source of elevated circulating prorenin levels in normal pregnancy. significance. Trans Am Clin Climatol Assoc 95: 93–104, 1983.
Am J Obstet Gynecol 155: 1223–1226, 1986. 79. Carlsson PO, Berne C, and Jansson L. Angiotensin II and the
58. Breault L, Lehoux JG, and Gallo-Payet N. The angiotensin AT2 endocrine pancreas: effects on islet blood flow and insulin secre-
receptor is present in the human fetal adrenal gland throughout the tion in rats. Diabetologia 41: 127–133, 1998.
second trimester of gestation. J Clin Endocrinol Metab 81: 3914 – 80. Cassis LA. Role of angiotensin II in brown adipose thermogenesis
3922, 1996. during cold acclimation. Am J Physiol Endocrinol Metab 265:
59. Brewster UC and Perazella MA. The renin-angiotensin-aldoste- E860 –E865, 1993.
rone system and the kidney: effects on kidney disease. Am J Med 81. Cassis LA and Dwoskin LP. Presynaptic modulation of neuro-
116: 263–272, 2004. transmitter release by endogenous angiotensin II in brown adipose
60. Brink M, Price SR, Chrast J, Bailey JL, Anwar A, Mitch WE, tissue. J Neural Transm Suppl 34: 129 –137, 1991.
and Delafontaine P. Angiotensin II induces skeletal muscle wast- 82. Cassis LA, English VL, Bharadwaj K, and Boustany CM. Dif-
ing through enhanced protein degradation and down-regulates au- ferential effects of local versus systemic angiotensin II in the
tocrine insulin-like growth factor I. Endocrinology 142: 1489 –1496, regulation of leptin release from adipocytes. Endocrinology 145:
2001. 169 –174, 2004.
61. Brosnihan KB, Li P, Ganten D, and Ferrario CM. Estrogen 83. Cassis LA, Fettinger MJ, Roe AL, Shenoy UR, and Howard G.
protects transgenic hypertensive rats by shifting the vasoconstric- Characterization and regulation of angiotensin II receptors in rat
tor-vasodilator balance of RAS. Am J Physiol Regul Integr Comp adipose tissue. Angiotensin receptors in adipose tissue. Adv Exp
Physiol 273: R1908 –R1915, 1997. Med Biol 396: 39 – 47, 1996.
62. Bruneval P, Hinglais N, Alhenc-Gelas F, Tricottet V, Corvol P, 84. Cassis LA, Lynch KR, and Peach MJ. Localization of angio-
Menard J, and Camilleri JP. Angiotensin I converting enzyme in tensinogen messenger RNA in rat aorta. Circ Res 62: 1259 –1262,
human intestine and kidney. Histochemistry 85: 73– 80, 1986. 1988.

85. Castren E, Kurihara M, Gutkind JS, and Saavedra JM. Specific specific expression of ACE. Am J Physiol Renal Physiol 284:
angiotensin II binding sites in the rat stellate and superior cervical F599 –F607, 2003.
ganglia. Brain Res 422: 347–351, 1987. 107. Coleman JK, Lee JI, Miller JM, and Nuttall AL. Changes in
86. Castren E, Kurihara M, and Saavedra JM. Autoradiographic cochlear blood flow due to intra-arterial infusions of angiotensin II
localization and characterization of angiotensin II binding sites in (3– 8) (angiotensin IV) in guinea pigs. Hear Res 119: 61– 68, 1998.
the spleen of rats and mice. Peptides 8: 737–742, 1987. 108. Correa FM, De Oliveira AM, Viswanathan M, and Saavedra
87. Catanzaro DF. Physiological relevance of renin/prorenin binding JM. Autoradiographic localization and characterization of angio-
and uptake. Hypertens Res 28: 97–105, 2005. tensin II receptor subtypes in the rat thymus. Peptides 15: 821– 824,
88. Cavasin MA, Rhaleb NE, Yang XP, and Carretero OA. Prolyl 1994.
oligopeptidase is involved in release of the antifibrotic peptide 109. Corvol P, Michaud A, Soubrier F, and Williams TA. Recent
Ac-SDKP. Hypertension 43: 1140 –1145, 2004. advances in knowledge of the structure and function of the angio-
89. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins tensin I converting enzyme. J Hypertens Suppl 13: S3–S10, 1995.
TA, and Albiston AL. The angiotensin IV/AT4 receptor. Cell Mol 110. Costerousse O, Allegrini J, Huang H, Bounhik J, and Alhenc-
Life Sci 61: 2728 –2737, 2004. Gelas F. Regulation of ACE gene expression and plasma levels
90. Chai SY, Mendelsohn FAO, and Paxinos G. Angiotensin con- during rat postnatal development. Am J Physiol Endocrinol Metab
verting enzyme in rat brain visualized by quantitative in vitro 267: E745–E753, 1994.
autoradiography. Neuroscience 20: 615– 627, 1987. 111. Costerousse O, Allegrini J, Huang W, and Alhenc-Gelas F.
91. Chan WP, Fung ML, Nobiling R, and Leung PS. Activation of Angiotensin I-converting enzyme (kininase II) in cardiovascular
local renin-angiotensin system by chronic hypoxia in rat pancreas. and renal regulations and diseases. Biol Res 31: 161–167, 1998.
Mol Cell Endocrinol 160: 107–114, 2000. 112. Cote F, Do TH, Laflamme L, Gallo JM, and Gallo-Payet N.
92. Chappell MC, Diz DI, and Jacobsen DW. Pharmacological char- Activation of the AT(2) receptor of angiotensin II induces neurite
outgrowth and cell migration in microexplant cultures of the cer-

acterization of angiotensin II binding sites in the canine pancreas.
Peptides 13: 313–318, 1992. ebellum. J Biol Chem 274: 31686 –31692, 1999.
93. Chappell MC, Milsted A, Diz DI, Brosnihan KB, and Ferrario 113. Cote F, Laflamme L, Payet MD, and Gallo-Payet N. Nitric
CM. Evidence for an intrinsic angiotensin system in the canine oxide, a new second messenger involved in the action of angioten-
pancreas. J Hypertens 9: 751–759, 1991. sin II on neuronal differentiation of NG108 –15 cells. Endocr Res 24:
94. Chen CY and Huang WC. Pressor and renal effects of intracere- 403– 407, 1998.
broventricularly administered angiotensins II and III in rats. Kid- 114. Coude G, Marois A, and Casanova C. Effects of angiotensin II on
ney Blood Press Res 23: 95–105, 2000. visual evoked potentials in the superior colliculus of juvenile rats.
95. Chen X, Li W, Yoshida H, Tsuchida S, Nishimura H, Takemoto Neuropeptides 34: 203–210, 2000.
F, Okubo S, Fogo A, Matsusaka T, and Ichikawa I. Targeting 115. Cox BE, Word RA, and Rosenfeld CR. Angiotensin II receptor
deletion of angiotensin type 1B receptor gene in the mouse. Am J characteristics and subtype expression in uterine arteries and myo-
Physiol Renal Fluid Electrolyte Physiol 272: F299 –F304, 1997. metrium during pregnancy. J Clin Endocrinol Metab 81: 49 –58,
1996.
96. Cheng ZJ, Vapaatalo H, and Mervaala E. Angiotensin II and
116. Cox HM, Cuthbert AW, and Munday KA. The effect of angio-
vascular inflammation. Med Sci Monit 11: RA194 –RA205, 2005.
tensin II upon electrogenic ion transport in rat intestinal epithelia.
97. Cheung WT, Yeung SY, Yiu AK, Ip TM, Wan DC, Luk SK, and
Br J Pharmacol 90: 393– 401, 1987.
Ho WK. Characterization of a functional AT1A angiotensin receptor
117. Cox SL, Trendelenburg AU, and Starke K. Prejunctional angio-
in pancreatoma AR4 –2J cells. Peptides 20: 829 – 836, 1999.
tensin receptors involved in the facilitation of noradrenaline re-
98. Chidambaram M, Duncan JA, Lai VS, Cattran DC, Floras JS,
lease in mouse tissues. Br J Pharmacol 127: 1256 –1262, 1999.
Scholey JW, and Miller JA. Variation in the renin angiotensin
118. Crabos M, Roth M, Hahn A, and Erne P. Characterization of
system throughout the normal menstrual cycle. J Am Soc Nephrol
angiotensin II receptors in cultured adult rat cardiac fibroblasts.
13: 446 – 452, 2002. Coupling to signaling systems and gene expression. J Clin Invest
99. Cigola E, Kajstura J, Li B, Meggs LG, and Anversa P. Angio- 2372–2378, 1994.
tensin II activates programmed myocyte cell death in vitro. Exp 119. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradski I,
Cell Res 231: 363–371, 1997. Scanga SE, Oliveira-Dos-Santos AJ, da Costa J, Zhang L, Pei
100. Cingolani HE, Perez NG, Aiello EA, and de Hurtado MC. Y, Scholey J, Ferrario CM, Manoukian AS, Chappel MC,
Intracellular signaling following myocardial stretch: an autocrine/ Backx PH, Yagie Y, and Penninger JM. Angiotensin-converting
paracrine loop. Regul Pept 128: 211–220, 2005. enzyme 2 is an essential regulator of heart function. Nature 417:
101. Cingolani OH, Yang XP, Liu YH, Villanueva M, Rhaleb NE, and 822– 828, 2002.
Carretero OA. Reduction of cardiac fibrosis decreases systolic 120. Crandall DL, Armellino DC, Busler DE, McHendry-Rinde B,
performance without affecting diastolic function in hypertensive and Kral JG. Angiotensin II receptors in human preadipocytes:
rats. Hypertension 43: 1067–1073, 2004. role in cell cycle regulation. Endocrinology 140: 154 –158, 1999.
102. Cipollone F, Fazia M, Iezzi A, Pini B, Cuccurullo C, Zucchelli 121. Crandall DL, Herzlinger HE, Saunders BD, Armellino DC, and
M, de CD, Ucchino S, Spigonardo F, De LM, Muraro R, Bei R, Kral JG. Distribution of angiotensin II receptors in rat and human
Bucci M, Cuccurullo F, and Mezzetti A. Blockade of the angio- adipocytes. J Lipid Res 35: 1378 –1385, 1994.
tensin II type 1 receptor stabilizes atherosclerotic plaques in hu- 122. Craven DJ, Warren AY, and Symonds EM. Generation of angio-
mans by inhibiting prostaglandin E2-dependent matrix metallopro- tensin I by human chorion-decidua in vitro. Am J Obstet Gynecol
teinase activity. Circulation 109: 1482–1488, 2004. 145: 744 –748, 1983.
103. Clausmeyer S, Reinecke A, Farrenkopf R, Unger T, and Pe- 123. Cullen JJ, Ephgrave KS, Broadhurst KA, and Booth B. Capto-
ters J. Tissue-specific expression of a rat-renin transcript lacking pril decreases stress ulceration without affecting gastric perfusion
the coding sequence for the prefragment and its stimulation by during canine hemorrhagic shock. J Trauma 37: 43– 49, 1994.
myocardial infarction. Endocrinology 141: 2963–2970, 2000. 124. Culler MD, Tarlatzis BC, Lightman A, Fernandez LA, DeCher-
104. Clausmeyer S, Sturzebecher R, and Peters J. An alternative ney AH, Negro-Vilar A, and Naftolin F. Angiotensin II-like im-
transcript of the rat renin gene can result in a truncated prorenin munoreactivity in human ovarian follicular fluid. J Clin Endocrinol
that is transported into adrenal mitochondria. Circ Res 84: 337–344, Metab 62: 613– 615, 1986.
1999. 125. Cullinane AB, Leung PS, Ortego J, Coca-Prados M, and Har-
105. Clyne CD, Nicol MR, MacDonald S, Williams BC, and Walker vey BJ. Renin-angiotensin system expression and secretory func-
SW. Angiotensin II stimulates growth and steroidogenesis in zona tion in cultured human ciliary body non-pigmented epithelium. Br J
fasciculata/reticularis cells from bovine adrenal cortex via the AT1 Ophthamol 86: 676 – 683, 2002.
receptor subtype. Endocrinology 132: 2206 –2212, 1993. 126. Cushman DW and Cheung HS. Concentrations of angiotensin-
106. Cole JM, Xiao H, Adams JW, Disher KM, Zhao H, and Bern- converting enzyme in tissues of the rat. Biochim Biophys Acta 250:
stein KE. New approaches to genetic manipulation of mice: tissue- 261–265, 1971.

127. Dale WE and Blaine EH. Effects of enalaprilat on neointimal 148. Dempsey PJ, McCallum ZT, Kent KM, and Cooper T. Direct
growth of cultured rabbit aorta following balloon injury. Can myocardial effects of angiotensin II. Am J Physiol 220: 477– 481,
J Physiol Pharmacol 77: 763–769, 1999. 1971.
128. Danilczyk U, Eriksson U, Oudit GY, and Penninger JM. Phys- 149. De Oliveira AM, Viswanathan M, Heemskerk FM, and Saave-
iological roles of angiotensin-converting enzyme 2. Cell Mol Life dra JM. Expression of a novel angiotensin II receptor subtype in
Sci 61: 2714 –2719, 2004. gerbil brain. Brain Res 705: 177–187, 1995.
129. Danser AH, Derkx FH, Schalekamp MA, Hense HW, Riegger 150. Depierre D, Bargetzi JP, and Roth M. Dipeptidyl carboxypepti-
GA, and Schunkert H. Determinants of interindividual variation dase from human seminal plasma. Biochim Biophys Acta 523:
of renin and prorenin concentrations: evidence for a sexual dimor- 469 – 476, 1978.
phism of (pro)renin levels in humans. J Hypertens 16: 853– 862, 151. Derkx FH, Alberda AT, de Jong FH, Zeilmaker FH, Makovitz
1998. JW, and Schalekamp MA. Source of plasma prorenin in early and
130. Danser AH, Koning MM, Admiraal PJ, Sassen LM, Derkx FH, late pregnancy: observations in a patient with primary ovarian
Verdouw PD, and Schalekamp MA. Production of angiotensins I failure. J Clin Endocrinol Metab 65: 349 –354, 1987.
and II at tissue sites in intact pigs. Am J Physiol Heart Circ Physiol 152. Deschepper CF. Angiotensinogen: hormonal regulation and rela-
263: H429 –H437, 1992. tive importance in the generation of angiotensin II. Kidney Int 46:
131. Danser AH, van den Dorpel MA, Deinum J, Derkx FH, 1561–1563, 1994.
Peperkamp E, de Jong PT, and Schalekamp MA. Prorenin in 153. Deschepper CF, Mellon SH, Cumin F, Baxter JD, and Ganong
vitreous and subretinal fluid of the human eye. Clin Exp Hypertens WF. Analysis by immunocytochemistry and in situ hybridization of
10: 1297–1299, 1988. renin and its mRNA in kidney, testis, adrenal, and pituitary of the
132. Danser AH, van Kats JP, Admiraal PJ, Derkx FH, Lamers JM, rat. Proc Natl Acad Sci USA 83: 7552–7556, 1986.
Verdouw PD, Saxena PR, and Schalekamp MA. Cardiac renin 154. De Silva PE, Husain A, Smeby RR, and Khairallah PA. Mea-
and angiotensins: uptake from plasma versus in situ synthesis.

surement of immunoreactive angiotensin peptides in rat tissues:
Hypertension 37– 48, 1994. some pitfalls in angiotensin II analysis. Anal Biochem 174: 80 – 87,
134. Danser AH, van Kesteren CA, Bax WA, Tavenier M, Derkx 1988.
FH, Saxena PR, and Schalekamp MA. Prorenin, renin, angio- 155. De Vito E, Guardia DC, and Cabrera RR. A renin-like enzyme in
tensinogen and ACE in normal or failing hearts: evidence for renin rat luteal tissue: evidence of local synthesis and its regulation
binding. Circulation 96: 220 –226, 1997. during pregnancy. J Endocrinol 128: 43– 49, 1991.
135. Daud AI, Bumpus FM, and Husain A. Evidence for selective 156. Dezso B, Jacobsen J, and Poulsen K. Evidence for the presence
expression of angiotensin II receptors on atretic follicles in the rat of angiotensins in normal, unstimulated alveolar macrophages and
ovary: an autoradiographic study. Endocrinology 122: 2727–2734, monocytes. J Hypertens 7: 5–11, 1989.
1988. 157. Dezso B, Nielsen AH, and Poulsen K. Identification of renin in
136. Daugherty A, Manning MW, and Cassis L. Antagonism of AT2 resident alveolar macrophages and monocytes: HPLC and immu-
receptors augments angiotensin II-induced abdominal aortic aneu-
nohistochemical study. J Cell Sci 91: 155–159, 1988.
rysms and atherosclerosis. Br J Pharmacol 134: 865– 870, 2001.
158. Diaz-Torga G, Gonzalez IA, Achaval-Zaia R, Libertun C, and
137. Davisson RL, Oliverio MI, Coffman TM, and Sigmund CD.
Becu-Villalobos D. Angiotensin II-induced Ca2⫹ mobilization and
Divergent functions of angiotensin II receptor isoforms in the
prolactin release in normal and hyperplastic pituitary cells. Am J
brain. J Clin Invest 106: 103–106, 2000.
Physiol Endocrinol Metab 274: E534 –E540, 1998.
138. Day MD and Owen DA. The interaction between angiotensin and
159. Dickinson DP, Gross KW, Piccini N, and Wilson CM. Evolution
sympathetically-induced vasoconstriction in the isolated perfused
and variation of renin genes in mice. Genetics 108: 651– 667, 1984.
central ear artery of the rabbit. Naunyn-Schmiedebergs Arch Exp
160. Diep QN, El Mabrouk M, Yue P, and Schiffrin EL. Effect of
Pathol Pharmacol 259: 164 –165, 1968.
AT(1) receptor blockade on cardiac apoptosis in angiotensin II-
139. De Carvalho F, Sun Y, and Weber KT. Angiotensin II receptor
blockade and myocardial fibrosis of the infarcted rat heart. J Lab induced hypertension. Am J Physiol Heart Circ Physiol 282:
Clin Med 129: 439 – 446, 1997. H1635–H1641, 2002.
140. Dechend R, Homuth V, Wallukat G, Kreuzer J, Park JK, 161. Diep QN, El Mabrouk M, Cohn JS, Endemann D, Amiri F,
Theuer J, Juepner A, Gulba DC, Mackman N, Haller H, and Virdis A, Neves MF, and Schiffrin EL. Structure, endothelial
Luft FC. AT(1) receptor agonistic antibodies from preeclamptic function, cell growth, and inflammation in blood vessels of angio-
patients cause vascular cells to express tissue factor. Circulation tensin II-infused rats: role of peroxisome proliferator-activated re-
101: 2382–2387, 2000. ceptor-gamma. Circulation 105: 2296 –2302, 2002.
141. Dechend R, Muller DN, Wallukat G, Homuth V, Krause M, 162. Diep QN, Li JS, and Schiffrin EL. In vivo study of AT(1) and
Dudenhausen J, and Luft FC. Activating auto-antibodies against AT(2) angiotensin receptors in apoptosis in rat blood vessels.
the AT1 receptor in preeclampsia. Autoimmune Rev 4: 61– 65, 2005. Hypertension 34: 617– 624, 1999.
142. De Gasparo M, Catt KJ, Inagami T, and Unger T. International 163. Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA,
Union of Pharmacology. XXIII. The angiotensin II receptors. Phar- and Pardo J. Cardiomyocyte apoptosis and cardiac angiotensin-
macol Rev 52: 415– 472, 2000. converting enzyme in spontaneously hypertensive rats. Hyperten-
143. Deinum J, Ronn B, Mathiesen E, Derkx FH, Hop WC, and sion 30: 1029 –1034, 1997.
Schalekamp MA. Increase in serum prorenin precedes onset of 164. Dinh DT, Frauman AG, Sourial M, Casley DJ, Johnston CI,
microalbuminuria in patients with insulin-dependent diabetes mel- and Fabiani ME. Identification, distribution, and expression of
litus. Diabetologia 42: 1006 –1010, 1999. angiotensin II receptors in the normal human prostate and benign
144. De Lannoy LM, Danser AH, van Kats JP, Schoemaker RG, prostatic hyperplasia. Endocrinology 142: 1349 –1356, 2001.
Saxena PR, and Schalekamp MA. Renin-angiotensin system 165. Dixon IM, Ju H, Jassal DS, and Peterson DJ. Effect of ramipril
components in the interstitial fluid of the isolated perfused rat and losartan on collagen expression in right and left heart after
heart: local production of angiotensin I. Hypertension 29: 1111– myocardial infarction. Mol Cell Biochem 165: 31– 45, 1996.
1117, 1997. 166. Diz DI and Ferrario CM. Bidirectional transport of angiotensin II
145. De los R, Labajos M, Manteca A, Morell M, and Souviron A. binding sites in the vagus nerve. Hypertension 11 Suppl I: I-139 –
Stimulatory action of angiotensin II on water and electrolyte trans- I-143, 1988.
port by the proximal colon of the rat. J Endocrinol 86: 35– 43, 1980. 167. Doggrell SA and Wanstall JC. Cardiac chymase: pathophysiolog-
146. Delpon E, Caballero R, Gomez R, Nunez L, and Tamargo J. ical role and therapeutic potential of chymase inhibitors. Can
Angiotensin II, angiotensin II antagonists and spironolactone and J Physiol Pharmacol 83: 123–130, 2005.
their modulation of cardiac repolarization. Trends Pharmacol Sci 168. Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini
26: 155–161, 2005. T, and Delbridge LM. Angiotensin II-mediated phenotypic cardi-
147. De Mello WC and Danser AH. Angiotensin II and the heart. omyocyte remodeling leads to age-dependent cardiac dysfunction
Hypertension 35: 1183–1188, 2000. and failure. Hypertension 46: 426 – 432, 2005.

169. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, 189. Esther CR, Howard TE, Marino EM, Goddard JM, Capecchi
Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, MR, and Bernstein KE. Mice lacking angiotensin-converting en-
Breitbart RE, and Acton S. A novel angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male
zyme-related carboxypeptidase (ACE2) converts angiotensin I to fertility. Lab Invest 74: 953–965, 1996.
angiotensin 1–9. Circ Res 87: E1–E9, 2000. 190. Falkenhahn MFF, Bohle RM, Zhou Y, Stauss HM, Bachmann S,
170. Dorey PG, King J, Munday KA, Parsons BJ, and Poat J. Intes- Danilov SM, and Unger T. Cellular distribution of angiotensin-
tinal fluid absorption in spontaneously hypertensive rats. J Physiol converting enzyme after myocardial infarction. Hypertension 25:
344: 1–9, 1983. 219 –226, 1995.
171. Duggan KA, Mendelsohn FAO, and Levens NR. Angiotensin 191. Farber HW, Center DM, Rounds S, and Danilov SM. Compo-
receptors and angiotensin I-converting enzyme in rat intestine. nents of the angiotensin system cause release of a neutrophil
Am J Physiol Gastrointest Liver Physiol 257: G504 –G510, 1989. chemoattractant from cultured bovine and human endothelial cells.
172. Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlof B, Eur Heart J 11 Suppl B: 100 –107, 1990.
Deanfield J, Diez J, Drexler H, Ferrari R, Van GW, Hansson L, 192. Feldmer M, Kaling M, Takahashi S, Mullins JJ, and Ganten D.
Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Luscher T, Glucocorticoid- and estrogen-responsive elements in the 5⬘-flank-
Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, ing region of the rat angiotensinogen gene. J Hypertens 9: 1005–
Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, 1012, 1991.
Vaughan D, and Weber M. The relevance of tissue angiotensin- 193. Felix D, Khosla MC, Barnes KL, Imboden H, Montani B, and
converting enzyme: manifestations in mechanistic and endpoint Ferrario CM. Neurophysiological responses to angiotensin-
data. Am J Cardiol 88: 1L–20L, 2001. (1O7). Hypertension 17: 1111–1114, 1991.
173. Dzau VJ, Brody T, Ellison KE, Pratt RE, and Ingelfinger JR. 194. Feral C, Benhaim A, and Leymarie P. Angiotensin II receptor
Tissue-specific regulation of renin expression in the mouse. Hyper- type 1 on granulosa and thecal cells of rabbit preovulatory follicles.

tension 9 Suppl III: III-36 –III-41, 1987. Biochim Biophys Acta 1284: 221–226, 1996.
174. Dzau VJ, Ellison KE, Brody T, Ingelfinger J, and Pratt RE. A 195. Feral C, Le Gall S, and Leymarie P. Angiotensin II modulates
comparative study of the distributions of renin and angiotensino- steroidogenesis in granulosa and theca in the rabbit ovary: its
gen messenger ribonucleic acids in rat and mouse tissues. Endo- possible involvement in atresia. Eur J Endocrinol 133: 747–753,
crinology 120: 2334 –2338, 1987. 1995.
175. Dzau VJ and Gibbons GH. Autocrine-paracrine mechanisms of 196. Fernandez LA, Tarlatzis BC, Rzasa PJ, Caride VJ, Laufer N,
vascular myocytes in systemic hypertension. Am J Cardiol 60: Negro-Vilar A, DeCherney AH, and Naftolin F. Renin-like ac-
99I–103I, 1987. tivity in ovarian follicular fluid. Fertil Steril 44: 219 –223, 1985.
176. Dzau VJ, Ingelfinger J, Pratt RE, and Ellison KE. Identification 197. Fernandez-Alfonso M, Martorana P, Licka I, van Even P,
of renin and angiotensinogen messenger RNA sequences in mouse Trobisch D, Schölkens B, and Paul M. Early induction of angio-
and rat brains. Hypertension 8: 544 –548, 1986. tensin-I-converting enzyme in rat carotid artery after balloon injury.
177. Dzau VJ and Pratt RE. Renin-angiotensin system: biology, phys- Hypertension 30: 272–277, 1997.
iology, and pharmacology. Heart Cardiovasc Syst 2: 1631–1662, 198. Fernandez-Pardal J, Chaud M, Viggiano M, Gimeno MF, and
1986. Gimeno AL. Converting enzyme activity in sow oviducts at differ-
178. Dzau VJ and Re R. Tissue angiotensin system in cardiovascular ent stages of the sex cycle. Influence of inhibitors of prostaglandin
medicine. A paradigm shift? Circulation 89: 493– 498, 1994. synthesis and its possible role in the inotropic effects of bradyki-
179. Ekker M, Tronik D, and Rougeon F. Extra-renal transcription of nin. Pharmacol Res Commun 18: 49 – 60, 1986.
the renin genes in multiple tissues of mice and rats. Proc Natl Acad 199. Ferrara N, Chen H, Davis-Smyth T, Gerber H, Nguyen T,
Sci USA 86: 5155–5158, 1989. Peers D, Chisholm V, Hillan KJ, and Schwall RH. Vascular
180. El-Dorry HA, MacGregor JS, and Soffer RL. Dipeptidyl car- endothelial growth factor is essential for corpus luteum angiogen-
boxypeptidase from seminal fluid resembles the pulmonary rather esis. Nature Med 4: 336 –340, 1998.
than the testicular isoenzyme. Biochem Biophys Res Commun 115: 200. Ferrario CM, Brosnihan KB, Diz DI, Jaiswal N, Khosla MC,
1096 –1100, 1983. Milsted A, and Tallant EA. Angiotensin-(1O7): a new hormone
181. El Ghissassi M, Thornton SN, and Nicolaidis S. Angiotensin of the angiotensin system. Hypertension 18 Suppl III: III-126 –III-
II-induced thirst, but not sodium appetite, via AT1 receptors in 133, 1991.
organum cavum prelamina terminalis. Am J Physiol Regul Integr 201. Ferrario CM and Chappell MC. Novel angiotensin peptides. Cell
Comp Physiol 268: R1401–R1405, 1995. Mol Life Sci 61: 2720 –2727, 2004.
182. Ellison KE, Ingelfinger JR, Pivor M, and Dzau VJ. Androgen 202. Ferrario CM, Dickinson CJ, and McCubbin JW. Central vaso-
regulation of rat renal angiotensinogen messenger RNA expression. motor stimulation by angiotensin. Clin Sci 39: 239 –245, 1970.
J Clin Invest 83: 1941–1945, 1989. 203. Ferrario CM, Santos RA, Brosnihan KB, Block CH, Schiavone
183. Engeli S, Gorzelniak K, Kreutz R, Runkel N, Distler A, and MT, Khosla MC, and Greene LJ. A hypothesis regarding the
Sharma AM. Co-expression of renin-angiotensin system genes in function of angiotensin peptides in the brain. Clin Exp Hypertens
human adipose tissue. J Hypertens 17: 555–560, 1999. 10 Suppl 1: 107–121, 1988.
184. Engeli S, Negrel R, and Sharma AM. Physiology and pathophys- 204. Field LJ and Gross KW. Ren-1 and Ren-2 loci are expressed in
iology of the adipose tissue renin-angiotensin system. Hyperten- mouse kidney. Proc Natl Acad Sci USA 82: 6196 – 6200, 1985.
sion 35: 1270 –1277, 2000. 205. Field LJ, McGowan R, Dickinson DP, and Gross KW. Tissue
185. Epstein AN, Fitzsimons JT, and Rolls BJ. Drinking induced by and gene specificity of mouse renin expression. Hypertension 6:
injection of angiotensin into the brain of the rat. J Physiol 210: 597– 603, 1984.
457– 474, 1970. 206. Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri
186. Erickson RH, Suzuki Y, Sedlmayer A, Song IS, and Kim YS. A, and Kajstura J. Myocyte death in streptozotocin-induced dia-
Rat intestinal angiotensin-converting enzyme: purification, proper- betes in rats is angiotensin II-dependent. Lab Invest 80: 513–527,
ties, expression, and function. Am J Physiol Gastrointest Liver 2000.
Physiol 263: G466 –G473, 1992. 207. Fischer M, Baessler A, and Schunkert H. Renin angiotensin
187. Erman A, Chen-Gal B, van Dijk DJ, Sulkes J, Kaplan B, Boner system and gender differences in the cardiovascular system. Car-
G, and Neri A. Ovarian angiotensin-converting enzyme activity in diovasc Res 53: 672– 677, 2002.
humans: relationship to estradiol, age, and uterine pathology. 208. Fleming I, Kohlstedt K, and Busse R. New fACEs to the renin-
J Clin Endocrinol Metab 81: 1104 –1107, 1996. angiotensin system. Physiology 20: 91–95, 2005.
188. Eshima K, Hirooka Y, Shigematsu H, Matsuo I, Koike G, Sakai 209. Flynn AJ, Quirk WS, Dengerink HA, and Wright JW. The
K, and Takeshita A. Angiotensin in the nucleus tractus solitarii effects of intracerebroventricularly administered angiotensin II on
contributes to neurogenic hypertension caused by chronic nitric blood pressure and cochlear blood flow in rats and guinea pigs.
oxide synthase inhibition. Hypertension 36: 259 –263, 2000. Hear Res 41: 249 –254, 1989.

210. Fordis CM, Megorden JS, Ropchak TG, and Keiser HR. Ab- 233. Goette A, Staack T, Rocken C, Arndt M, Geller JC, Huth C,
sence of renin-like activity in rat aorta and microvessels. Hyper- Ansorge S, Klein HU, and Lendeckel U. Increased expression of
tension 5: 635– 641, 1983. extracellular signal-regulated kinase and angiotensin-converting
211. Foresta C, Indino M, Manoni F, and Scandellari C. Angioten- enzyme in human atria during atrial fibrillation. J Am Coll Cardiol
sin-converting enzyme content of human spermatozoa and its re- 35: 1669 –1677, 2000.
lease during capacitation. Fertil Steril 47: 1000 –1003, 1987. 234. Gohlke P, Pees C, and Unger T. AT2 receptor stimulation in-
212. Foresta C, Mioni R, Rossato M, Varotto A, and Zorzi M. creases aortic cyclic GMP in SHRSP by a kinin-dependent mecha-
Evidence for the involvement of sperm angiotensin converting nism. Hypertension 31: 349 –355, 1998.
enzyme in fertilization. Int J Androl 14: 333–339, 1991. 235. Goldhaber SZ, Hennekens CH, Spark RF, Evans DA, Rosner
213. Forhead AJ, Melvin R, Balouzet V, and Fowden AL. Develop- B, Taylor JO, and Kass EH. Plasma renin substrate, renin activ-
mental changes in plasma angiotensin-converting enzyme concen- ity, and aldosterone levels in a sample of oral contraceptive users
tration in fetal and neonatal lambs. Reprod Fertil Dev 10: 393–398, from a community survey. Am Heart J 107: 119 –122, 1984.
1998. 236. Goldwin B, Khan MJ, Shivapuja B, Seidman MD, and Quirk
214. Freshour JR, Chase SE, and Vikstrom KL. Gender differences WS. Sarthran preserves cochlear microcirculation and reduces
in cardiac ACE expression are normalized in androgen-deprived temporary threshold shifts after noise exposure. Otolaryngol Head
male mice. Am J Physiol Heart Circ Physiol 283: H1997–H2003, Neck Surg 118: 576 –583, 1998.
2002. 237. Gordon MS, Chin WW, and Shupnik MA. Regulation of angio-
215. Galabov PG. Ultrastructural localization of angiotensin II-like im- tensinogen gene expression by estrogen. J Hypertens 10: 361–366,
munoreactivity (A II-LI) in the vegetative networks of the spinal 1992.
cord of the guinea pig. J Auton Nerv Syst 40: 215–222, 1992. 238. Goulter AB, Goddard MJ, Allen JC, and Clark KL. ACE2 gene
216. Gallagher PE, Li P, Lenhart JR, Chappell MC, and Brosnihan expression is up-regulated in the human failing heart. BMC Med 2:
KB. Estrogen regulation of angiotensin-converting enzyme mRNA. 19, 2004.

Hypertension 33: 323–328, 1999. 239. Gray MO, Long CS, Kalinyak JE, Li HT, and Karliner JS.
217. Galli SJ. New concepts about the mast cell. N Engl J Med 328: Angiotensin II stimulates cardiac myocyte hypertrophy via para-
257–265, 1993. crine release of TGF-beta 1 and endothelin-1 from fibroblasts.
218. Ganong WF. Reproduction and the renin-angiotensin system. Neu- Cardiovasc Res 40: 352–363, 1998.
rosci Biobehav Rev 19: 241–250, 1995. 240. Griendling KK, Minieri CA, Ollerenshaw JD, and Alexander
219. Ganten D, Marquez-Julio A, Granger P, Hayduk K, Karsunky RW. Angiotensin II stimulates NADH and NADPH oxidase activity
KP, Boucher R, and Genest J. Renin in the dog brain. Am J in cultured vascular smooth muscle cells. Circ Res 74: 1141–1148,
Physiol 221: 1733–1737, 1971. 1994.
220. Ganten D, Minnich JL, Granger P, Hayduk K, Brecht HM, 241. Gross V, Milia AF, Plehm R, Inagami T, and Luft FC. Long-term
Barbeau A, Boucher R, and Genest J. Angiotensin-forming en- blood pressure telemetry in AT2 receptor-disrupted mice. J Hyper-
zyme in brain tissue. Science 173: 64 – 65, 1971. tens 18: 955–961, 2000.
221. Gaudet E, Godwin SJ, and Head GA. Effects of central infusion 242. Grove KL and Speth RC. Rat epididymis contains functional
of ANG II and losartan on the cardiac baroreflex in rabbits. Am J angiotensin II receptors. Endocrinology 125: 223–230, 1989.
Physiol Heart Circ Physiol 278: H558 –H566, 2000. 243. Gyurko R, Kimura B, Kurian P, Crews FT, and Phillips MI.
222. Gehlert DR, Speth RC, and Wamsley JK. Distribution of [125I]an- Angiotensin II receptor subtypes play opposite roles regulating
giotensin II binding sites in the rat brain: a quantitative autoradio- phosphatidylinositol hydrolysis in rat skin slices. Biochem Biophys
graphic study. Neuroscience 18: 837– 856, 1986. Res Commun 186: 285–292, 1992.
223. Geisterfer AA, Peach MJ, and Owens GK. Angiotensin II in- 244. Hackenthal E, Hackenthal R, and Hilgenfeldt U. Isorenin, pseu-
duces hypertrophy, not hyperplasia, of cultured rat aortic smooth dorenin, cathepsin D and renin. A comparative enzymatic study of
muscle cells. Circ Res 62: 749 –756, 1988. angiotensin-forming enzymes. Biochim Biophys Acta 522: 574 –588,
224. Ghiani BU and Masini MA. Angiotensin II binding sites in the rat 1978.
pancreas and their modulation after sodium loading and depletion. 245. Hackenthal E, Paul M, Ganten D, and Taugner R. Morphology,
Comp Biochem Physiol A Physiol 111: 439 – 444, 1995. physiology, and molecular biology of renin secretion. Physiol Rev
225. Ghosh P, Dahms NM, and Kornfeld S. Mannose 6-phosphate 70: 1067–1116, 1990.
receptors: new twists in the tale. Nat Rev Mol Cell Biol 4: 202–212, 246. Hagaman JR, Moyer JS, Bachman ES, Sibony M, Magyar PL,
2003. Welch JE, Smithies O, Krege JH, and O’Brien DA. Angiotensin-
226. Giacchetti G, Faloia E, Sardu C, Camilloni MA, Mariniello B, converting enzyme and male fertility. Proc Natl Acad Sci USA 95:
Gatti C, Garrapa GG, Guerrieri M, and Mantero F. Gene 2552–2557, 1998.
expression of angiotensinogen in adipose tissue of obese patients. 247. Hagemann A. Solution of methodological problems in prorenin
Int J Obes Relat Metab Disord 24 Suppl 2: S142–S143, 2000. measurement and investigations of tissue renin-angiotensin sys-
227. Gibbons GH, Pratt RE, and Dzau VJ. Vascular smooth muscle tems in the female reproductive tract. Dan Med Bull 44: 486 – 498,
cell hypertrophy vs. hyperplasia. Autocrine transforming growth 1997.
factor-beta 1 expression determines growth response to angioten- 248. Hagemann A, Nielsen AH, Assey RJ, Hyttel P, Boland MP,
sin II. J Clin Invest 90: 456 – 461, 1992. Roche JF, and Poulsen K. Prorenin and active renin concentra-
228. Gimonet V, Bussieres L, Medjebeur AA, Gasser B, Lelongt B, tions in ovarian follicular fluid increase after the LH peak in super-
and Laborde K. Nephrogenesis and angiotensin II receptor sub- ovulated heifers. Clin Exp Pharmacol Physiol 21: 639 – 648, 1994.
types gene expression in the fetal lamb. Am J Physiol Renal 249. Hagemann A, Nielsen AH, and Poulsen K. The uteroplacental
Physiol 274: F1062–F1069, 1998. renin-angiotensin system: a review. Exp Clin Endocrinol 102: 252–
229. Gironacci MM, Vatta M, Rodriguez F, Fernandez BE, and 261, 1994.
Pena C. Angiotensin-(1O7) reduces norepinephrine release 250. Hall JE. Historical perspective of the renin-angiotensin system.
through a nitric oxide mechanism in rat hypothalamus. Hyperten- Mol Biotechnol 24: 27–39, 2003.
sion 35: 1248 –1252, 2000. 251. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GJ, and
230. Glorioso N, Atlas SA, Laragh JH, Jewelewicz R, and Sealey Van GH. Tissue distribution of ACE2 protein, the functional recep-
JE. Prorenin in high concentrations in human ovarian follicular tor for SARS coronavirus. A first step in understanding SARS
fluid. Science 233: 1422–1424, 1986. pathogenesis. J Pathol 203: 631– 637, 2004.
231. Goette A, Arndt M, Rocken C, Spiess A, Staack T, Geller JC, 252. Han NL and Sim MK. Hypothalamic angiotensin receptor sub-
Huth C, Ansorge S, Klein HU, and Lendeckel U. Regulation of types in normotensive and hypertensive rats. Am J Physiol Heart
angiotensin II receptor subtypes during atrial fibrillation in hu- Circ Physiol 275: H703–H709, 1998.
mans. Circulation 101: 2678 –2681, 2000. 253. Hanna IR, Taniyama Y, Szocs K, Rocic P, and Griendling KK.
232. Goette A and Lendeckel U. Nonchannel drug targets in atrial NAD(P)H oxidase-derived reactive oxygen species as mediators of
fibrillation. Pharmacol Ther 102: 17–36, 2004. angiotensin II signaling. Antioxid Redox Signal 4: 899 –914, 2002.

254. Hannan RE, Davis EA, and Widdop RE. Functional role of 274. Hinojosa-Laborde C, Craig T, Zheng W, Ji H, Haywood JR,
angiotensin II AT2 receptor in modulation of AT1 receptor-medi- and Sandberg K. Ovariectomy augments hypertension in aging
ated contraction in rat uterine artery: involvement of bradykinin female Dahl salt-sensitive rats. Hypertension 44: 405– 409, 2004.
and nitric oxide. Br J Pharmacol 140: 987–995, 2003. 275. Hirai K, Song K, Kanehara H, Shiota N, Ueda H, Kim S,
255. Harding JW, Cook VI, Miller-Wing AV, Hanesworth JM, Sar- Miyazaki H, Katsuoka Y, and Miyazaki M. Pituitary-dependent
dinia MF, Hall KL, Stobb JW, Swanson GN, Coleman JK, and expression of the testicular angiotensin II receptor and its subtypes
Wright JW. Identification of an AII(3– 8) [AIV] binding site in in rats. Int J Androl 21: 177–185, 1998.
guinea pig hippocampus. Brain Res 583: 340 –343, 1992. 276. Hirose S, Yokosawa H, Inagami T, and Workman KJ. Renin and
256. Harding JW, Sullivan MJ, Hanesworth JM, Cushing LL, and prorenin in hog brain: ubiquitous distribution and high concentra-
Wright JW. Inability of [125I]Sar1, Ile8-angiotensin II to move tion in pituitary and pineal. Brain Res 191: 489 – 499, 1980.
between the blood and cerebrospinal fluid compartments. J Neu- 277. Hirsch AT, Talsness CE, Schunkert H, Paul M, and Dzau VJ.
rochem 50: 554 –557, 1988. Tissue-specific activation of cardiac angiotensin converting en-
257. Harmer D, Gilbert M, Borman R, and Clark KL. Quantitative zyme in experimental heart failure. Circ Res 69: 475– 482, 1991.
mRNA expression profiling of ACE 2, a novel homologue of angio- 278. Hirsch AT, Talsness CE, Smith AD, Schunkert H, Ingelfinger
tensin converting enzyme. FEBS Lett 532: 107–110, 2002. JR, and Dzau VJ. Differential effects of captopril and enalapril on
258. Harp JB and DiGirolamo M. Components of the renin-angioten- tissue renin-angiotensin systems in experimental heart failure. Cir-
sin system in adipose tissue: changes with maturation and adipose culation 86: 1566 –1574, 1992.
mass enlargement. J Gerontol A Biol Sci Med Sci 50: B270 –B276, 279. Hoffmann S. Cardiac-specific overexpression of angiotensin II
1995. type 1 receptor in transgenic rats. Methods Mol Med 112: 389 – 403,
259. Harris RC and Cheng HF. The intrarenal renin-angiotensin sys- 2005.
tem: a paracrine system for the local control of renal function 280. Hoffmann S, Krause T, van Geel PP, Willenbrock R, Pagel I,

separate from the systemic axis. Exp Nephrol 4 Suppl 1: 2–7, 1996. Pinto Y, Buikema H, van Gilst WH, Lindschau C, Paul M,
260. Harvey PJ, Morris BL, Miller JA, and Floras JS. Estradiol Inagami T, Ganten D, and Urata H. Overexpression of the hu-
induces discordant angiotensin and blood pressure responses to man angiotensin II type 1 receptor in the rat heart augments load
orthostasis in healthy postmenopausal women. Hypertension 45: induced cardiac hypertrophy. J Mol Med 79: 601– 608, 2001.
399 – 405, 2005. 281. Hohlbrugger G, Pschorr J, and Dahlheim H. Angiotensin I con-
261. Harvey PJ, Wing LM, Savage J, and Molloy D. The effects of verting enzyme in the ejaculate of fertile and infertile men. Fertil
different types and doses of oestrogen replacement therapy on Steril 41: 324 –325, 1984.
clinic and ambulatory blood pressure and the renin-angiotensin 282. Hohlbrugger G, Schweisfurth H, and Dahlheim H. Angiotensin
system in normotensive postmenopausal women. J Hypertens 17: I converting enzyme in rat testis, epididymis and vas deferens
405– 411, 1999. under different conditions. J Reprod Fertil 65: 97–103, 1982.
262. Hassager C, Riis BJ, Strom V, Guyene TT, and Christiansen C. 283. Hohle S, Spitznagel H, Rascher W, Culman J, and Unger T.
The long-term effect of oral and percutaneous estradiol on plasma Angiotensin AT1 receptor-mediated vasopressin release and drink-
renin substrate and blood pressure. Circulation 76: 753–758, 1987. ing are potentiated by an AT2 receptor antagonist. Eur J Pharma-
263. Hatch M, Freel RW, and Vaziri ND. Local upregulation of colonic col 275: 277–282, 1995.
angiotensin II receptors enhances potassium excretion in chronic 284. Hokimoto S, Yasue H, Fujimoto K, Nakao K, and Myamoto F.
renal failure. Am J Physiol Renal Physiol 274: F275–F282, 1998. Expression of angiotensin converting enzyme in remaining viable
264. Hauser W, Johren O, and Saavedra JM. Characterization and myocytes in human ventricles after myocardial infarction. Circu-
distribution of angiotensin II receptor subtypes in the mouse brain. lation 94: 1513–1518, 1996.
Eur J Pharmacol 348: 101–114, 1998. 285. Hollenberg NK and Williams GH. Angiotensin as a renal, adre-
265. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, nal, and cardiovascular hormone: responses to saralasin in normal
Yusuf S, and Connolly SJ. Prevention of atrial fibrillation with man and in essential and secondary hypertension. Kidney Int 9
angiotensin-converting enzyme inhibitors and angiotensin receptor Suppl: S29 –S35, 1979.
blockers: a meta-analysis. J Am Coll Cardiol 45: 1832–1839, 2005. 286. Holubarsch C, Hasenfuss G, Schmidt-Schweda S, Knorr A,
266. Healey JS, Morillo CA, and Connolly SJ. Role of the renin- Pieske B, Ruf T, Fasol R, and Just H. Angiotensin I and II exert
angiotensin-aldosterone system in atrial fibrillation and cardiac inotropic effects in atrial but not in ventricular human myocar-
remodeling. Curr Opin Cardiol 20: 31–37, 2005. dium. An in vitro study under physiological experimental condi-
267. Heinrikson RL, Hui J, Zurcher-Neely H, and Poorman RA. A tions. Circulation 88: 1228 –1237, 1993.
structural model to explain the partial catalytic activity of human 287. Hosli L, Hosli E, Heuss L, and Rojas J. Electrophysiological
prorenin. Am J Hypertens 2: 367–380, 1989. evidence for receptors for vasoactive intestinal peptide and angio-
268. Hellmann W, Suzuki F, Ohkubo H, Nakanishi S, Ludwig G, and tensin II on astrocytes of cultured rat central nervous system.
Ganten D. Angiotensinogen gene expression in extrahepatic rat Neurosci Lett 102: 217–222, 1989.
tissues: application of a solution hybridization assay. Naunyn- 288. Hosoda Y, Winarto A, Iwanaga T, and Kuwahara A. Mode of
Schmiedeberg’s Arch Pharmacol 338: 327–331, 1988. action of ANG II on ion transport in guinea pig distal colon. Am J
269. Hermann K, Phillips MI, Hilgenfeldt U, and Raizada MK. Bio- Physiol Gastrointest Liver Physiol 278: G625–G634, 2000.
synthesis of angiotensinogen and angiotensins by brain cells in 289. Hosomi N, Nishiyama A, Ban CR, Naya T, Takahashi T, Kohno
primary culture. J Neurochem 51: 398 – 405, 1988. M, and Koziol JA. Angiotensin type 1 receptor blockage improves
270. Hermann K, Raizada MK, Sumners C, and Philips MI. Presence ischemic injury following transient focal cerebral ischemia. Neu-
of renin in primary neuronal and glial cells from rat brain. Brain roscience 134: 225–231, 2005.
Res 437: 205–213, 1987. 290. Howard RB, Pucell AG, Bumpus FM, and Husain A. Rat ovarian
271. Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Sou- renin: characterization and changes during the estrous cycle. En-
brier F, Dubay C, Cartwright P, De GB, Julier C, and Takahasi docrinology 123: 2331–2340, 1988.
S. Chromosomal mapping of two genetic loci associated with 291. Howard TE, Shai SY, Langford KG, Martin BM, and Bernstein
blood-pressure regulation in hereditary hypertensive rats. Nature KE. Transcription of testicular angiotensin-converting enzyme
353: 521–529, 1991. (ACE) is initiated within the 12th intron of the somatic ACE gene.
272. Hilgers KF, Kuczera M, Wilhelm MJ, Wiecek A, Ritz E, Ganten Mol Cell Biol 10: 4294 – 4302, 1990.
D, and Mann JF. Angiotensin formation in the isolated rat hind- 292. Huang XC, Richards EM, and Sumners C. Mitogen-activated
limb. J Hypertens 7: 789 –798, 1989. protein kinases in rat brain neuronal cultures are activated by
273. Hilgers KF, Veelken R, Muller DN, Kohler H, Hartner A, angiotensin II type 1 receptors and inhibited by angiotensin II type
Botkin SR, Stumpf C, Schmieder RE, and Gomez RA. Renin 2 receptors. J Biol Chem 271: 15635–15641, 1996.
uptake by the endothelium mediates vascular angiotensin forma- 293. Hubert C, Houot AM, Corvol P, and Soubrier F. Structure of
tion. Hypertension 38: 243–248, 2001. the angiotensin I-converting enzyme gene. Two alternate promot-

ers correspond to evolutionary steps of a duplicated gene. J Biol 314. Jaiswal AK, Panda JN, Kumar MV, and Singh LN. Age related
Chem 266: 15377–15383, 1991. development of angiotensin converting enzyme in testes and epi-
294. Hunt RA, Ciuffo GM, Saavedra JM, and Tucker DC. Quantifi- didymis of rat. Andrologia 15: 347–349, 1983.
cation and localisation of angiotensin II receptors and angiotensin 315. Jan Danser AH and Saris JJ. Prorenin uptake in the heart: a
converting enzyme in the developing rat heart. Cardiovasc Res 29: prerequisite for local angiotensin generation? J Mol Cell Cardiol 34:
834 – 840, 1995. 1463–1472, 2002.
295. Hutchinson HG, Hein L, Fujinaga M, and Pratt RE. Modulation 316. Janiak P, Libert O, and Vilaine JP. Role of the renin-angiotensin
of vascular development and injury by angiotensin II. Cardiovasc system in neointima formation after injury in rabbits. Hypertension
Res 41: 689 –700, 1999. 24: 671– 678, 1994.
296. Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, 317. Jaszewski R, Tolia V, Ehrinpreis MN, Bodzin JH, Peleman RR,
Tada Y, Koura Y, Nishiyama A, Okada H, Uddin MN, Nabi AH, Korlipara R, and Weinstock JV. Increased colonic mucosal an-
Ishida Y, Inagami T, and Saruta T. Inhibition of diabetic ne- giotensin I and II concentrations in Crohn’s colitis. Gastroenterol-
phropathy by a decoy peptide corresponding to the “handle” region ogy 98: 1543–1548, 1990.
for nonproteolytic activation of prorenin. J Clin Invest 114: 1128 – 318. Jensen BL, Stubbe J, Madsen K, Nielsen FT, and Skott O. The
1135, 2004. renin-angiotensin system in kidney development: role of COX-2 and
297. Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, adrenal steroids. Acta Physiol Scand 181: 549 –559, 2004.
and Inagami T. Angiotensin II type 2 receptor is essential for left 319. Jikihara H, Poisner AM, Hirsch R, and Handwerger S. Human
ventricular hypertrophy and cardiac fibrosis in chronic angiotensin uterine decidual macrophages express renin. J Clin Endocrinol
II-induced hypertension. Circulation 104: 346 –351, 2001. Metab 80: 1273–1277, 1995.
298. Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo 320. Jin XH, Wang ZQ, Siragy HM, Guerrant RL, and Carey RM.
A, Niimura F, Ichikawa I, Hogan BL, and Inagami T. Effects on Regulation of jejunal sodium and water absorption by angiotensin

blood pressure and exploratory behaviour of mice lacking angio- subtype receptors. Am J Physiol Regul Integr Comp Physiol 275:
tensin II type-2 receptor. Nature 377: 748 –750, 1995. R515–R523, 1998.
299. Ihara Y, Taii S, and Mori T. Expression of renin and angio- 321. Johnson AR, Skidgel RA, Gafford JT, and Erdos EG. Enzymes
tensinogen genes in the human placental tissues. Endocrinol Jpn in placental microvilli: angiotensin I converting enzyme, angiotensi-
34: 887– 896, 1987. nase A, carboxypeptidase, and neutral endopeptidase (“enkephali-
300. Ikegami H, Yamada T, and Suzuki T. Angiotensin II-induced nase”). Peptides 5: 789 –796, 1984.
depolarizations in hamster submandibular ganglion neurons. Bull 322. Johren O, Hauser W, and Saavedra JM. Chemical lesion of the
Tokyo Dent Coll 41: 29 –34, 2000. inferior olive reduces [125I]sarcosine1-angiotensin II binding to AT2
301. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao receptors in the cerebellar cortex of young rats. Brain Res 793:
176 –186, 1998.
R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC,
323. Johren O, Inagami T, and Saavedra JM. Localization of AT2
Hein L, Uhlig S, Slutsky AS, Jiang C, and Penninger JM.
angiotensin II receptor gene expression in rat brain by in situ
Angiotensin-converting enzyme 2 protects from severe acute lung
hybridization histochemistry. Brain Res 37: 192–200, 1996.
failure. Nature 436: 112–116, 2005.
324. Johren O, Inagami T, and Saavedra JM. AT1A, AT1B, and AT2
302. Inagami T. Recent progress in molecular and cell biological stud-
angiotensin II receptor subtype gene expression in rat brain. Neu-
ies of angiotensin receptors. Curr Opin Nephrol Hypertens 4:
roreport 6: 2549 –2552, 1995.
47–54, 1995.
325. Johren O and Saavedra JM. Expression of AT1A and AT1B angio-
303. Intebi AD, Flaxman MS, Ganong WF, and Deschepper CF.
tensin II receptor messenger RNA in forebrain of 2-wk-old rats.
Angiotensinogen production by rat astroglial cells in vitro and in
Am J Physiol Endocrinol Metab 271: E104 –E112, 1996.
vivo. Neuroscience 34: 545–554, 1990. 326. Johren O, Sanvitto GL, Egidy G, and Saavedra JM. Angiotensin
304. Itskovitz J, Bruneval P, Soubrier F, Thaler I, Corvol P, and II AT1A receptor mRNA expression is induced by estrogen-proges-
Sealey JE. Localization of renin gene expression to monkey ovar- terone in dopaminergic neurons of the female rat arcuate nucleus.
ian theca cells by in situ hybridization. J Clin Endocrinol Metab 75: J Neurosci 17: 8283– 8292, 1997.
1374 –1380, 1992. 327. Jones BH, Standridge MK, and Moustaid N. Angiotensin II
305. Itskovitz J, Rubattu S, Rosenwaks Z, Liu HC, and Sealey JE. increases lipogenesis in 3T3-L1 and human adipose cells. Endocri-
Relationship of follicular fluid prorenin to oocyte maturation, ste- nology 138: 1512–1519, 1997.
roid levels, and outcome of in vitro fertilization. J Clin Endocrinol 328. Jonsson JR, Game PA, Head RJ, and Frewin DB. The expres-
Metab 72: 165–171, 1991. sion and localisation of the angiotensin-converting enzyme mRNA
306. Iwai N and Inagami T. Identification of two subtypes in the rat in human adipose tissue. Blood Press 3: 72–75, 1994.
type I angiotensin II receptor. FEBS Lett 298: 257–260, 1992. 329. Joy MD and Lowe RD. Evidence for a medullary site of action in
307. Iwai N and Inagami T. Quantitative analysis of renin gene expres- the cardiovascular response to angiotensin II. J Physiol 206: 41P–
sion in extrarenal tissues by polymerase chain reaction method. 42P, 1970.
J Hypertens 10: 717–724, 1992. 330. Kagiyama S, Tsuchihashi T, Abe I, Matsumura K, and Fu-
308. Iwai N, Inagami T, Ohmichi N, and Kinoshita M. Renin is jishima M. Antisense inhibition of angiotensinogen attenuates va-
expressed in rat macrophage/monocyte cells. Hypertension 27: sopressin release in the paraventricular hypothalamic nucleus of
399 – 403, 1996. spontaneously hypertensive rats. Brain Res 829: 120 –124, 1999.
309. Iwai N, Izumi M, Inagami T, and Kinoshita A. Induction of renin 331. Kakinuma Y, Hama H, Sugiyama F, Yagami K, Goto K, Mu-
in medial smooth muscle cells by balloon injury. Hypertension 29: rakami K, and Fukamizu A. Impaired blood-brain barrier func-
1044 –1050, 1997. tion in angiotensinogen-deficient mice. Nat Med 4: 1078 –1080, 1998.
310. Iyer SN, Ferrario CM, and Chappell MC. Angiotensin-(1O7) 332. Kalenga MK, Thomas K, de Gasparo M, and De Hertogh R.
contributes to the antihypertensive effects of blockade of the renin- Determination of renin, angiotensin converting enzyme and angio-
angiotensin system. Hypertension 31: 356 –361, 1998. tensin II levels in human placenta, chorion and amnion from
311. Jackson TR, Blair AC, Marshall J, Goedert M, and Hanley MR. women with pregnancy induced hypertension. Clin Endocrinol 44:
The mas oncogene encodes an angiotensin receptor. Nature 335: 429 – 433, 1996.
437– 440, 1988. 333. Kalinyak JE, Hoffman AR, and Perlman AJ. Ontogeny of an-
312. Jacob MP. Extracellular matrix remodeling and matrix metallo- giotensinogen mRNA and angiotensin II receptors in rat brain and
proteinases in the vascular wall during aging and in pathological liver. J Endocrinol Invest 14: 647– 653, 1991.
conditions. Biomed Pharmacother 57: 195–202, 2003. 334. Kanehara H, Song K, Hirai K, Ueda H, Shiota N, Azuma H,
313. Jaiswal A, Joshi P, Kumar MV, Panda JN, and Singh LN. Katsuoka Y, Miyazaki H, and Miyazaki M. Involvement of an-
Angiotensin converting enzyme in the testis and epididymis of giotensin II receptor subtypes during testicular development in
mammals. Andrologia 16: 410 – 416, 1984. rats. Int J Androl 21: 186 –195, 1998.

335. Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, receptor antagonist TCV-116 induces regression of hypertensive
and Carlsson LM. Human adipose tissue expresses angiotensino- left ventricular hypertrophy in vivo and inhibits the intracellular
gen and enzymes required for its conversion to angiotensin II. signaling pathway of stretch-mediated cardiomyocyte hypertrophy
J Clin Endocrinol Metab 83: 3925–3929, 1998. in vitro. Circulation 89: 2204 –2211, 1994.
336. Kaschina E and Unger T. Angiotensin AT1/AT2 receptors: regula- 358. Kon Y, Hashimoto Y, Kitagawa H, Sugimura M, and Murakami
tion, signalling and function. Blood Press 12: 70 – 88, 2003. K. Renin immunohistochemistry in the adrenal gland of the mouse
337. Kawakami M, Makimoto K, Fukuse S, and Takahashi H. Au- fetus and neonate. Anat Rec 227: 124 –131, 1990.
toregulation of cochlear blood flow. A comparison of cerebral 359. Kostenis E, Milligan G, Christopoulos A, Sanchez-Ferrer CF,
blood flow with muscular blood flow. Eur Arch Otorhinolaryngol Heringer-Walther S, Sexton PM, Gembardt F, Kellett E, Mar-
248: 471– 474, 1991. tini L, Vanderheyden P, Schultheiss HP, and Walther T. G-
338. Keidar S. Angiotensin, LDL peroxidation and atherosclerosis. Life protein-coupled receptor Mas is a physiological antagonist of the
Sci 63: 1–11, 1998. angiotensin II type 1 receptor. Circulation 111: 1806 –1813, 2005.
339. Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, 360. Kouyama R, Suganami T, Nishida J, Tanaka M, Toyoda T,
Best CF, Jennette JC, Coffman TM, Maeda N, and Smithies O. Kiso M, Chiwata T, Miyamoto Y, Yoshimasa Y, Fukamizu A,
Genetic control of blood pressure and the angiotensinogen locus. Horiuchi M, Hirata Y, and Ogawa Y. Attenuation of diet-induced
Proc Natl Acad Sci USA 92: 2735–2739, 1995. weight gain and adiposity through increased energy expenditure in
340. Kim JA, Berliner JA, and Nadler JL. Angiotensin II increases mice lacking angiotensin II type 1a receptor. Endocrinology 146:
monocyte binding to endothelial cells. Biochem Biophys Res Com- 3481–3489, 2005.
mun 226: 862– 868, 1996. 361. Krege JH, John SW, Langenbach LL, Hodgin JB, Hagaman JR,
341. Kim S, Shinjo M, Fukamizu A, Miyazaki H, Usuki S, and Bachman ES, Jennette JC, O’Brien DA, and Smithies O. Male-
Murakami K. Identification of renin and renin messenger RNA female differences in fertility and blood pressure in ACE-deficient
sequence in rat ovary and uterus. Biochem Biophys Res Commun mice. Nature 375: 146 –148, 1995.

142: 169 –175, 1987. 362. Kreutz R, Fernandez-Alfonso MS, Liu Y, Ganten D, and Paul
342. Kim S, Shinjo M, Tada M, Usuki S, Fukamizu A, Miyazaki H, M. Induction of cardiac angiotensin I-converting enzyme with di-
and Murakami K. Ovarian renin gene expression is regulated by etary NaCl-loading in genetically hypertensive and normotensive
follicle-stimulating hormone. Biochem Biophys Res Commun 146: rats. J Mol Med 73: 243–248, 1995.
989 –995, 1987. 363. Krob HA, Vinsant SL, Ferrario CM, and Friedman DP. Angio-
343. Kim S, Tokuyama M, Hosoi M, and Yamamoto K. Adrenal and tensin-(1O7) immunoreactivity in the hypothalamus of the (mRen-
circulating renin-angiotensin system in stroke-prone hypertensive 2d)27 transgenic rat. Brain Res 798: 36 – 45, 1998.
rats. Hypertension 20: 280 –291, 1992. 364. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang
344. Kim S, Whelan J, Claycombe K, Reath DB, and Moustaid- P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell
Moussa N. Angiotensin II increases leptin secretion by 3T3-L1 and M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D,
human adipocytes via a prostaglandin-independent mechanism. J Qin C, Jiang C, and Penninger JM. A crucial role of angiotensin
Nutr 132: 1135–1140, 2002. converting enzyme 2 (ACE2) in SARS coronavirus-induced lung
345. Kimura B, Sumners C, and Phillips MI. Changes in skin angio- injury. Nat Med 11: 875– 879, 2005.
tensin II receptors in rats during wound healing. Biochem Biophys 365. Kubo T, Yamaguchi H, Tsujimura M, Hagiwara Y, and Fuku-
Res Commun 187: 1083–1090, 1992. mori R. Blockade of angiotensin receptors in the anterior hypo-
346. Kisley LR, Sakai RR, and Fluharty SJ. Estrogen decreases hy- thalamic preoptic area lowers blood pressure in DOCA-salt hyper-
pothalamic angiotensin II AT1 receptor binding and mRNA in the tensive rats. Hypertens Res 23: 109 –118, 2000.
female rat. Brain Res 844: 34 – 42, 1999. 366. Kuji N, Sueoka K, Miyazaki T, Tanaka M, Oda T, Kobayashi T,
347. Kitami Y, Okura T, Marumoto K, Wakamiya R, and Hiwada K. and Yoshimura Y. Involvement of angiotensin II in the process of
Differential gene expression and regulation of type-1 angiotensin II gonadotropin-induced ovulation in rabbits. Biol Reprod 55: 984 –
receptor subtypes in the rat. Biochem Biophys Res Commun 188: 991, 1996.
446 – 452, 1992. 367. Kumar RS, Thekkumkara TJ, and Sen GC. The mRNAs encod-
348. Kitazono T, Padgett RC, Armstrong ML, Tompkins PK, and ing the two angiotensin-converting isozymes are transcribed from
Heistad DD. Evidence that angiotensin II is present in human the same gene by a tissue-specific choice of alternative transcrip-
monocytes. Circulation 91: 1129 –1134, 1995. tion initiation sites. J Biol Chem 266: 3854 –3862, 1991.
349. Klickstein LB, Kaempfer CE, and Wintroub BU. The granulo- 368. Kunert-Radek J, Stepien H, Komorowski J, and Pawlikowski
cyte-angiotensin system. Angiotensin I-converting activity of ca- M. Stimulatory effect of angiotensin II on the proliferation of
thepsin G. J Biol Chem 257: 15042–15046, 1982. mouse spleen lymphocytes in vitro is mediated via both types of
350. Knock GA, Sullivan MH, McCarthy A, Elder MG, Polak JM, angiotensin II receptors. Biochem Biophys Res Commun 198:
and Wharton J. Angiotensin II (AT1) vascular binding sites in 1034 –1039, 1994.
human placentae from normal-term, preeclamptic and growth re- 369. Kushiku K, Yamada H, Shibata K, Tokunaga R, Katsuragi T,
tarded pregnancies. J Pharmacol Exp Ther 271: 1007–1015, 1994. and Furukawa T. Upregulation of immunoreactive angiotensin II
351. Koch-Weser J. Myocardial actions of angiotensin. Circ Res 14: release and angiotensinogen mRNA expression by high-frequency
337–344, 1964. preganglionic stimulation at the canine cardiac sympathetic gan-
352. Koch-Weser J. Nature of the inotropic action of angiotensin on glia. Circ Res 88: 110 –116, 2001.
ventricular myocardium. Circ Res 16: 230 –237, 1965. 370. Lake-Bruse KD and Sigmund CD. Transgenic and knockout mice
353. Kohlstedt K, Brandes RP, Muller-Esterl W, Busse R, and to study the renin-angiotensin system and other interacting vaso-
Fleming I. Angiotensin-converting enzyme is involved in outside-in active pathways. Curr Hypertens Rep 2: 211–216, 2000.
signaling in endothelial cells. Circ Res 94: 60 – 67, 2004. 371. Lamparter S, Sun Y, and Weber KT. Angiotensin II receptor
354. Kohlstedt K, Busse R, and Fleming I. Signaling via the angio- blockade during gestation attenuates collagen formation in the
tensin-converting enzyme enhances the expression of cyclooxygen- developing rat heart. Cardiovasc Res 43: 165–172, 1999.
ase-2 in endothelial cells. Hypertension 45: 126 –132, 2005. 372. Lanzillo JJ, Dasarathy Y, Stevens J, Bardin CW, and Fanburg
355. Kohlstedt K, Shoghi F, Muller-Esterl W, Busse R, and Fleming BL. Human testicular angiotensin-converting enzyme is a mixture
I. CK2 phosphorylates the angiotensin-converting enzyme and reg- of two molecular weight forms. Only one is similar to the seminal
ulates its retention in the endothelial cell plasma membrane. Circ plasma enzyme. Biochem Biophys Res Commun 128: 457– 463,
Res 91: 749 –756, 2002. 1985.
356. Kohn FM, Miska W, and Schill WB. Release of angiotensin- 373. Laragh JH. The renin system and four lines of hypertension re-
converting enzyme (ACE) from human spermatozoa during capac- search. Hypertension 20: 267–279, 1992.
itation and acrosome reaction. J Androl 16: 259 –265, 1995. 374. Laragh JH, Sealey JE, Ledingham JG, and Newton MA. Oral
357. Kojima M, Shiojima I, Yamazaki T, Komuro I, Zou Z, Wang Y, contraceptives. Renin, aldosterone, and high blood pressure. JAMA
Mizuno T, Ueki K, Tobe K, and Kadowaki T. Angiotensin II 201: 918 –922, 1967.

375. Lattion AL, Soubrier F, Allegrini J, Hubert C, Corvol P, and chemical and electrophysiological studies. Biochim Biophys Acta
Alhenc-Gelas F. The testicular transcript of the angiotensin I-con- 1357: 65–72, 1997.
verting enzyme encodes for the ancestral, non-duplicated form of 395. Leung PS, Chan HC, and Wong PY. Immunohistochemical local-
the enzyme. FEBS Lett 252: 99 –104, 1989. ization of angiotensin II in the mouse pancreas. Histochem J 30:
376. Lavoie JL, Bianco RA, Sakai K, Keen HL, Ryan MJ, and Sig- 21–25, 1998.
mund CD. Transgenic mice for studies of the renin-angiotensin 396. Leung PS and Chappell MC. A local pancreatic renin-angiotensin
system in hypertension. Acta Physiol Scand 181: 571–577, 2004. system: endocrine and exocrine roles. Int J Biochem Cell Biol 35:
377. Lavoie JL and Sigmund CD. Minireview: overview of the renin- 838 – 846, 2003.
angiotensin system—an endocrine and paracrine system. Endocri- 397. Leung S, Wong TP, and Sernia C. Angiotensinogen expression by
nology 144: 2179 –2183, 2003. rat epididymis: evidence for an intrinsic, angiotensin-generating
378. Lebrun CJ, Blume A, Herdegen T, Seifert K, Bravo R, and system. Mol Cell Endocrinol 155: 115–122, 1999.
Unger T. Angiotensin II induces a complex activation of transcrip- 398. Levens NR. Response of rat jejunum to angiotensin III: pharma-
tion factors in the rat brain: expression of Fos, Jun and Krox cology and mechanism of action. Am J Physiol Gastrointest Liver
proteins. Neuroscience 65: 93–99, 1995. Physiol 245: G511–G518, 1983.
379. Leckie BJ, Birnie G, and Carachi R. Renin in Wilms’ tumor: 399. Levens NR. Response of isolated rat jejunum to angiotensin pep-
prorenin as an indicator. J Clin Endocrinol Metab 79: 1742–1746, tides. Am J Physiol Gastrointest Liver Physiol 251: G559 –G566,
1994. 1986.
380. Lee HU, Campbell DJ, and Habener JF. Developmental expres- 400. Levens NR, Peach MJ, and Carey RM. Interactions between
sion of the angiotensinogen gene in rat embryos. Endocrinology angiotensin peptides and the sympathetic nervous system mediat-
121: 1335–1342, 1987. ing intestinal sodium and water absorption in the rat. J Clin Invest
381. Lee MA, Böhm M, Paul M, and Ganten D. Tissue renin-angio- 67: 1197–1207, 1981.
tensin systems: their role in cardiovascular disease. Circulation 87

401. Levens NR, Peach MJ, and Carey RM. Role of the intrarenal
Suppl IV: 7–13, 1993. renin-angiotensin system in the control of renal function. Circ Res
382. Lee YA, Liang CS, Lee MA, and Lindpaintner K. Local stress, 48: 157–167, 1981.
not systemic factors, regulate gene expression of the cardiac renin- 402. Levens NR, Peach MJ, Carey RM, Poat JA, and Munday KA.
angiotensin system in vivo: a comprehensive study of all its com- Changes in an electroneutral transport process mediated by angio-
ponents in the dog. Proc Natl Acad Sci USA 93: 11035–11040, 1996. tensin II in the rat distal colon in vivo. Endocrinology 108: 1497–
383. Le Gall S, Feral C, and Leymarie P. Renin-angiotensin system of 1504, 1981.
the uterus and ovary in mammalian females. Reprod Nutr Dev 33: 403. Levy BI. Can angiotensin II type 2 receptors have deleterious
185–198, 1993. effects in cardiovascular disease? Implications for therapeutic
384. Lenkei Z, Corvol P, and Llorens-Cortes C. The angiotensin blockade of the renin-angiotensin system. Circulation 109: 8 –13,
receptor subtype AT1A predominates in rat forebrain areas involved 2004.
in blood pressure, body fluid homeostasis and neuroendocrine
404. Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C,
control. Brain Res 30: 53– 60, 1995.
Duriez M, Poitevin P, and Samuel JL. Chronic blockade of
385. Lenkei Z, Nuyt AM, Grouselle D, Corvol P, and Llorens-
AT2-subtype receptors prevents the effect of angiotensin II on the
Cortes C. Identification of endocrine cell populations expressing
rat vascular structure. J Clin Invest 98: 418 – 425, 1996.
the AT1B subtype of angiotensin II receptors in the anterior pitu-
405. Lewis DI and Coote JH. Angiotensin II in the spinal cord of the
itary. Endocrinology 140: 472– 477, 1999.
rat and its sympatho-excitatory effects. Brain Res 614: 1–9, 1993.
386. Le Noble FA, Schreurs NH, van Straaten HW, Slaaf DW, Smits
406. Lewis GP and Reit E. The action of angiotensin and bradykinin on
JF, Rogg H, and Struijker-Boudier HA. Evidence for a novel
the superior cervical ganglion of the cat. J Physiol 179: 538 –553,
angiotensin II receptor involved in angiogenesis in chick embryo
1965.
chorioallantoic membrane. Am J Physiol Regul Integr Comp
Physiol 264: R460 –R465, 1993. 407. Li P, Chen PM, Wang SW, and Chen LY. Time-dependent expres-
387. Le Noble FAC, Hekking JWM, Van Straaten HWM, Slaaf DW, sion of chymase and angiotensin converting enzyme in the hamster
and Struyker Boudier HA. Angiotensin II stimulates angiogenesis heart under pressure overload. Hypertens Res 25: 757–762, 2002.
in the chorio-allantoic membrane of the chick embryo. Eur J Phar- 408. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA,
macol 195: 305–306, 1991. Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC,
388. Lenz T, James GD, Laragh JH, and Sealey JE. Prorenin secre- Choe H, and Farzan M. Angiotensin-converting enzyme 2 is a
tion from human placenta perfused in vitro. Am J Physiol Endo- functional receptor for the SARS coronavirus. Nature 426: 450 –
crinol Metab 260: E876 –E882, 1991. 454, 2003.
389. Lenz T, Sealey JE, August P, James GD, and Laragh JH. Tissue 409. Li X, Shams M, Zhu J, Khalig A, Wilkes M, Whittle M, Barnes
levels of active and total renin, angiotensinogen, human chorionic N, and Ahmed A. Cellular localization of AT1 receptor mRNA and
gonadotropin, estradiol, and progesterone in human placentas protein in normal placenta and its reduced expression in intrauter-
from different methods of delivery. J Clin Endocrinol Metab 69: ine growth restriction. Angiotensin II stimulates the release of
31–37, 1989. vasorelaxants. J Clin Invest 101: 442– 454, 1998.
390. Lenz T, Sealey JE, and Tewksbury DA. Regional distribution of 410. Li XF and Ahmed A. Compartmentalization and cyclic variation of
the angiotensinogens in human placenta. Placenta 14: 695– 699, immunoreactivity of renin and angiotensin converting enzyme in
1993. human endometrium throughout the menstrual cycle. Hum Reprod
391. Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra 12: 2804 –2809, 1997.
A, Kajstura J, and Anversa P. Stretch-mediated release of angio- 411. Lightman A, Deschepper CF, Mellon SH, Ganong WF, and
tensin II induces myocyte apoptosis by activating p53 that en- Naftolin F. In situ hybridization identifies renin mRNA in the rat
hances the local renin-angiotensin system and decreases the Bcl- corpus luteum. Gynecol Endocrinol 1: 227–233, 1987.
2-to-Bax protein ratio in the cell. J Clin Invest 101: 1326 –1342, 412. Lightman A, Tarlatzis BC, Rzasa PJ, Culler MD, Caride VJ,
1998. Negro-Vilar AF, Lennard D, DeCherney AH, and Naftolin F.
392. Leung PS, Chan HC, Fu LX, Leung PY, Chew SB, and Wong PY. The ovarian renin-angiotensin system: renin-like activity and angio-
Angiotensin II receptors: localization of type I and type II in rat tensin II/III immunoreactivity in gonadotropin-stimulated and un-
epididymides of different developmental stages. J Membr Biol 157: stimulated human follicular fluid. Am J Obstet Gynecol 156: 808 –
97–103, 1997. 816, 1987.
393. Leung PS, Chan HC, Fu LX, and Wong PY. Localization of 413. Lin SY and Goodfriend TL. Angiotensin receptors. Am J Physiol
angiotensin II receptor subtypes AT1 and AT2 in the pancreas of 218: 1319 –1328, 1970.
rodents. J Endocrinol 153: 269 –274, 1997. 414. Lind RW, Swanson LW, and Ganten D. Organization of angio-
394. Leung PS, Chan HC, Fu LX, Zhou WL, and Wong PY. Angioten- tensin II immunoreactive cells and fibers in the rat central nervous
sin II receptors, AT1 and AT2 in the rat epididymis. Immunocyto- system. Neuroendocrinology 40: 2–24, 1985.

415. Lindpaintner K and Ganten D. The cardiac renin-angiotensin 436. Marshall RP. The pulmonary renin-angiotensin system. Curr
system: an appraisal of present experimental and clinical evidence. Pharm Des 9: 715–722, 2003.
Circ Res 68: 905–921, 1991. 437. Maru I, Ohta Y, Murata K, and Tsukada Y. Molecular cloning
416. Lindpaintner K, Jin M, Wilhelm MJ, Suzuki F, Linz W, Schoel- and identification of N-acyl-D-glucosamine 2-epimerase from por-
kens BA, and Ganten D. Intracardiac generation of angiotensin cine kidney as a renin-binding protein. J Biol Chem 271: 16294 –
and its physiologic role. Circulation 77 Suppl 1: I-18 –I-23, 1988. 16299, 1996.
417. Lindpaintner K, Lu W, Neidermajer N, Schieffer B, Just H, 438. Massiera F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu
Ganten D, and Drexler H. Selective activation of cardiac angio- A, Gasc JM, Quignard-Boulange A, Negrel R, Ailhaud G, Sey-
tensinogen gene expression in post-infarction ventricular remodel- doux J, Meneton P, and Teboul M. Adipose angiotensinogen is
ing in the rat. J Mol Cell Cardiol 25: 133–143, 1993. involved in adipose tissue growth and blood pressure regulation.
418. Lindstedt KA and Kovanen PT. Mast cells in vulnerable coronary FASEB J 15: 2727–2729, 2001.
plaques: potential mechanisms linking mast cell activation to 439. Massiera F, Seydoux J, Geloen A, Quignard-Boulange A, Tur-
plaque erosion and rupture. Curr Opin Lipidol 15: 567–573, 2004. ban S, Saint-Marc P, Fukamizu A, Negrel R, Ailhaud G, and
419. Lippoldt A, Bunnemann B, Ueki A, Rosen L, Cintra A, Has- Teboul M. Angiotensinogen-deficient mice exhibit impairment of
selrot U, Metzger R, Hilgenfeldt U, Brosnihan B, and Ganten diet-induced weight gain with alteration in adipose tissue develop-
D. On the plasticity of the cerebellar renin-angiotensin system: ment and increased locomotor activity. Endocrinology 142: 5220 –
localization of components and effects of mechanical perturbation.
5225, 2001.
Brain Res 668: 144 –159, 1994.
440. Mathai M, Evered MD, and McKinley MJ. Intracerebroventric-
420. Loot AE, Roks AJ, Henning RH, Tio RA, Suurmeijer AJ,
ular losartan inhibits postprandial drinking in sheep. Am J Physiol
Boomsma F, and van Gilst WH. Angiotensin-(1O7) attenuates
Regul Integr Comp Physiol 272: R1055–R1059, 1997.
the development of heart failure after myocardial infarction in rats.
Circulation 105: 1548 –1550, 2002. 441. Matsubara H, Shibasaki Y, Ogigaki M, Mori Y, Masaki H,

421. Lucius R, Gallinat S, Rosenstiel P, Herdegen T, Sievers J, and Kosaki A, Tsutsumi Y, Uchiyama Y, Fujiyama S, Nose A, Iba O,
Unger T. The angiotensin II type 2 (AT2) receptor promotes axonal Tateishi E, Hasegawa K, and Horiuchi M. Effect of angiotensin
regeneration in the optic nerve of adult rats. J Exp Med 188: II type 2 receptor on tyrosine kinase Pyk2 and c-Jun NH2-terminal
661– 670, 1998. kinase via SHP-1 tyrosine phosphatase activity: evidence from
422. Ludtke FE, Golenhofen K, and Schubert F. Angiotensin II vascular-targeted mice of AT2 receptor. Biochem Biophys Res
stimulates human gastric smooth muscle in vitro. J Auton Phar- Commun 282: 1085–1091, 2000.
macol 9: 139 –147, 1989. 442. Matsubara S, Saito K, Kizawa Y, Sano M, Osawa M, Iwamoto
423. Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, and K, and Murakami H. Evidence for the AT1 subtype of the angio-
Bryer-Ash M. Increased plasma inactive renin in diabetes mellitus. tensin II receptor in the rat submandibular gland. Biol Pharm Bull
A marker of microvascular complications. N Engl J Med 312: 23: 1185–1188, 2000.
1412–1417, 1985. 443. Meffert S, Stoll M, Steckelings UM, Bottari SP, and Unger T.
424. Luft FC. Proinflammatory effects of angiotensin II and endothelin: The angiotensin II AT2 receptor inhibits proliferation and promotes
targets for progression of cardiovascular and renal diseases. Curr differentiation in PC12W cells. Mol Cell Endocrinol 122: 59 – 67,
Opin Nephrol Hypertens 11: 59 – 66, 2002. 1996.
425. Lumbers ER. Angiotensin and aldosterone. Regul Pept 80: 91–100, 444. Menard J, Bouhnik J, Clauser E, Richoux JP, and Corvol P.
1999. Biochemistry and regulation of angiotensinogen. Clin Exp Hyper-
426. Luoh HF and Chan SH. Participation of AT1 and AT2 receptor tens 5: 1005–1019, 1983.
subtypes in the tonic inhibitory modulation of baroreceptor reflex 445. Mendelsohn FA, Chai SY, and Dunbar M. In vitro autoradio-
response by endogenous angiotensins at the nucleus tractus soli- graphic localization of angiotensin-converting enzyme in rat brain
tarii in the rat. Brain Res 782: 73– 82, 1998. using 125I-labelled MK351A. J Hypertens Suppl 2: S41–S44, 1984.
427. Lynch KR, Hawelu-Johnson CL, and Guyenet PG. Localization 446. Merabet L, de Gasparo M, and Casanova C. Dose-dependent
of brain angiotensinogen mRNA by hybridization histochemistry. inhibitory effects of angiotensin II on visual responses of the rat
Mol Brain Res 2: 149 –158, 1987. superior colliculus: AT1 and AT2 receptor contributions. Neuropep-
428. Ma R, Schultz HD, and Wang W. Chronic central infusion of ANG tides 31: 469 – 481, 1997.
II potentiates cardiac sympathetic afferent reflex in dogs. Am J 447. Metsarinne KP, Pekonen F, and Fyhrquist FY. Localization of
Physiol Heart Circ Physiol 277: H15–H22, 1999. renin substrate in fetoplacental tissue. Acta Endocrinol 123: 113–
429. Maassen Van Den Brink A, De VR, Saxena PR, Schalekamp 117, 1990.
MA, and Danser AH. Vasoconstriction by in situ formed angio- 448. Miller CC, Carter AT, Brooks JI, Lovell-Badge RH, and Bram-
tensin II: role of ACE and chymase. Cardiovasc Res 44: 407– 415, mar WJ. Differential extra-renal expression of the mouse renin
1999. genes. Nucleic Acids Res 17: 3117–3128, 1989.
430. MacGregor DP, Murone C, Song K, Allen AM, Paxinos G, and
449. Miyazaki Y, Tsuchida S, Fogo A, and Ichikawa I. The renal
Mendelsohn FA. Angiotensin II receptor subtypes in the human
lesions that develop in neonatal mice during angiotensin inhibition
central nervous system. Brain Res 675: 231–240, 1995.
mimic obstructive nephropathy. Kidney Int 55: 1683–1695, 1999.
431. Machado RD, Santos RA, and Andrade SP. Mechanisms of
450. Moe OW, Alpern RJ, and Henrich WL. The renal proximal tubule
angiotensin (1O7)-induced inhibition of angiogenesis. Am J
Physiol Regul Integr Comp Physiol 280: R994 –R1000, 2001. renin-angiotensin system. Semin Nephrol 13: 552–557, 1993.
432. Malhotra R, Sadoshima J, Brosius F, and Izumo S. Mechanical 451. Moeller I, Chai SY, MacGregor DP, Aldred GP, and Mendel-
stretch and angiotensin II differentially upregulate the renin-angio- sohn FA. Localization and quantitation of angiotensin AT1 and AT2
tensin-system in cardiac myocytes in vitro. Circ Res 85: 137–146, receptors in the pregnant and non-pregnant sheep uterus. Regul
1999. Pept 61: 213–218, 1996.
433. Marchand EL, Der SS, Hamet P, and deBlois D. Caspase-de- 452. Moeller I, Chai SY, Oldfield BJ, McKinley MJ, Casley D, and
pendent cell death mediates the early phase of aortic hypertrophy Mendelsohn FA. Localization of angiotensin IV binding sites to
regression in losartan-treated spontaneously hypertensive rats. motor and sensory neurons in the sheep spinal cord and hindbrain.
Circ Res 92: 777–784, 2003. Brain Res 701: 301–306, 1995.
434. Maric C, Aldred GP, Harris PJ, and Alcorn D. Angiotensin II 453. Moeller I, Lew RA, Mendelsohn FA, Smith AI, Brennan ME,
inhibits growth of cultured embryonic renomedullary interstitial Tetaz TJ, and Chai SY. The globin fragment LVV-hemorphin-7 is
cells through the AT2 receptor. Kidney Int 53: 92–99, 1998. an endogenous ligand for the AT4 receptor in the brain. J Neuro-
435. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, chem 68: 2530 –2537, 1997.
Delafontaine P, and Bernstein KE. Direct stimulation of Jak/ 454. Moeller I, Paxinos G, Mendelsohn FA, Aldred GP, Casley D,
STAT pathway by the angiotensin II AT1 receptor. Nature 375: and Chai SY. Distribution of AT4 receptors in the Macaca fascicu-
247–250, 1995. laris brain. Brain Res 712: 307–324, 1996.

455. Moffett RB. Angiotensinogen in cerebrospinal fluid corresponds 476. Naftolin F, Andrade-Gordon P, Pellicer A, Palumbo A, Apa R,
chromatographically to the gamma-form of plasma angiotensino- Zreik T, Yoon TK, and DeCherney A. Angiotensin II: does it have
gen. J Neurochem 49: 841– 845, 1987. a direct obligate role in ovulation? Science 245: 870 – 871, 1989.
456. Mohan J, Moudgal RP, and Singh NB. Angiotensin converting 477. Nagata M, Tanimoto K, Fukamizu A, Kon Y, Sugiyama F,
enzyme activity in female reproductive tract of domestic fowl Yagami K, Murakami K, and Watanabe T. Nephrogenesis and
(Gallus domesticus) and its interactions with semen. Indian J Exp renovascular development in angiotensinogen-deficient mice. Lab
Biol 31: 636 – 637, 1993. Invest 75: 745–753, 1996.
457. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, 478. Naruse K, Murakoshi M, Osamura RY, Naruse M, Toma H,
Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Watanabe K, Demura H, Inagami T, and Shizume K. Immuno-
Walter U, Forstermann U, Meinertz T, Griendling K, and histological evidence for renin in human endocrine tissues. J Clin
Munzel T. Effects of angiotensin II infusion on the expression and Endocrinol Metab 61: 172–177, 1985.
function of NAD(P)H oxidase and components of nitric oxide/ 479. Naruse M, Naruse K, Kurimoto F, Sakurai H, Yoshida S, Toma
cGMP signaling. Circ Res 90: E58 –E65, 2002. H, Ishii T, Obana K, Demura H, and Inagami T. Evidence for the
458. Monti J, Schinke M, Bohm M, Ganten D, Bader M, and Bricca existence of des-Asp1-angiotensin II in human uterine and adrenal
G. Glial angiotensinogen regulates brain angiotensin II receptors in tissues. J Clin Endocrinol Metab 61: 480 – 483, 1985.
transgenic rats TGR(ASrAOGEN). Am J Physiol Regul Integr 480. Naruse M, Naruse K, Shizume K, and Inagami T. Gonadotropin-
dependent renin in the rat testes. Proc Soc Exp Biol Med 177:
Comp Physiol 280: R233–R240, 2001.
337–342, 1984.
459. Morgan T, Craven C, Nelson L, Lalouel JM, and Ward K.
481. Naruse M, Wasada T, Naruse K, Yoshimoto T, Omori Y, and
Angiotensinogen T235 expression is elevated in decidual spiral
Demura H. Pathophysiological significance of plasma total renin
arteries. J Clin Invest 100: 1406 –1415, 1997.
and prorenin in patients with diabetes mellitus. Endocr J 42: 225–
460. Morgan T, Craven C, and Ward K. Human spiral artery renin- 233, 1995.

angiotensin system. Hypertension 32: 683– 687, 1998. 482. Navar LG, Kobori H, and Prieto-Carrasquero M. Intrarenal
461. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H, angiotensin II and hypertension. Curr Hypertens Rep 5: 135–143,
Kaneda Y, Ogihara T, and Dzau VJ. Evidence for direct local 2003.
effect of angiotensin in vascular hypertrophy. J Clin Invest 94: 483. Nederfors T, Dahlof C, Ericsson T, and Twetman S. Effects of
978 –984, 1994. the antihypertensive drug captopril on human salivary secretion
462. Morishita R, Gibbons GH, Ellison KE, Nakajima M, Zhang L, rate and composition. Eur J Oral Sci 103: 351–354, 1995.
Kaneda Y, Ogihara T, and Dzau VJ. Single intraluminal delivery 484. Neudeck H, Schuster C, Hildebrandt R, Oney T, Stiemer B,
of antisense cdc2 kinase and proliferating-cell nuclear antigene Hopp H, and Graf R. Histochemical evaluation of placental an-
oligonucleotides results in chronic inhibition of neointimal hyper- giotensinase A in pre-eclampsia: enzyme activity in villous tropho-
plasia. Proc Natl Acad Sci USA 90: 8474 – 8478, 1993. blast indicates an enhanced likelihood of gestational proteinuric
463. Morishita R, Gibbons S, Kaneda Y, Ogihara T, and Dzau VJ. hypertension. Placenta 17: 155–163, 1996.
Novel and effective gene transfer technique for study of vascular- 485. Neuss M, Regitz-Zagrosek V, Hildebrandt A, and Fleck E.
renin angiotensin system. J Clin Invest 91: 2580 –2585, 1993. Human cardiac fibroblasts express an angiotensin receptor with
464. Moritz KM, Boon WC, and Wintour EM. Aldosterone secretion unusual binding characteristics which is coupled to cellular prolif-
by the mid-gestation ovine fetus: role of the AT2 receptor. Mol Cell eration. Biochem Biophys Res Commun 204: 1334 –1339, 1994.
Endocrinol 157: 153–160, 1999. 486. Ng KK and Vane JR. Conversion of angiotensin I to angiotensin II.
465. Morris BJ. Molecular biology of renin. I: Gene and protein struc- Nature 216: 762–766, 1967.
ture, synthesis and processing. J Hypertens 10: 209 –214, 1992. 487. Nguyen G, Bouzhir L, Delarue F, Rondeau E, and Sraer JD.
466. Morris BJ and Reid IA. The distribution of angiotensinogen in Evidence of a renin receptor on human mesangial cells: effects on
dog brain studied by cell fractionation. Endocrinology 103: 492– PAI1 and cGMP. Nephrologie 19: 411– 416, 1998.
500, 1978. 488. Nguyen G, Burckle CA, and Sraer JD. Renin/prorenin-receptor
467. Morris RS, Francis MM, Do YS, Hsueh WA, Lobo RA, and biochemistry and functional significance. Curr Hypertens Rep 6:
Paulson RJ. Angiotensin II (AII) modulation of steroidogenesis by 129 –132, 2004.
luteinized granulosa cells in vitro. J Assist Reprod Genet 11: 117– 489. Nguyen G, Delarue F, Berrou J, Rondeau E, and Sraer JD.
122, 1994. Specific receptor binding of renin on human mesangial cells in
468. Mukhopadhyay AK and Brunswig-Spickenheier B. Follicular culture increases plasminogen activator inhibitor-1 antigen. Kid-
maturation and atresia–possible role of intraovarian regulatory ney Int 50: 1897–1903, 1996.
factors. J Reprod Fertil Suppl 50: 105–112, 1996. 490. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, and
469. Mukhopadhyay AK, Holstein K, Szkudlinski M, Brunswig- Sraer JD. Pivotal role of the renin/prorenin receptor in angioten-
Spickenheier B, and Leidenberger FA. The relationship be- sin II production and cellular responses to renin. J Clin Invest 109:
1417–1427, 2002.
tween prorenin levels in follicular fluid and follicular atresia in
491. Nicholls J and Peiris M. Good ACE, bad ACE do battle in lung
bovine ovaries. Endocrinology 129: 2367–2375, 1991.
injury, SARS. Nat Med 11: 821– 822, 2005.
470. Muller DN, Fischli W, Clozel J, Hilgers KF, Bohlender J,
492. Nickenig G, Baumer AT, Grohe C, Kahlert S, Strehlow K,
Menard J, Busjahn A, Ganten D, and Luft FC. Local angiotensin
Rosenkranz S, Stablein A, Beckers F, Smits JF, Daemen MJ,
II generation in the rat heart. Role of renin uptake. Circ Res 82: Vetter H, and Bohm M. Estrogen modulates AT1 receptor gene
13–20, 1998. expression in vitro and in vivo. Circulation 97: 2197–2201, 1998.
471. Mullins JJ, Peters J, and Ganten D. Fulminant hypertension in 493. Nickenig G, Geisen G, Vetter H, and Sachinidis A. Character-
transgenic rats harbouring the mouse Ren-2 gene. Nature 344: ization of angiotensin receptors on human skin fibroblasts. J Mol
541–544, 1990. Med 75: 217–222, 1997.
472. Mullins JJ, Sigmund CD, Kane-Haas C, Wu C, Pacholec F, 494. Nickenig G, Jung O, Strehlow K, Zolk O, Linz W, Scholkens
Zeng Q, and Gross KW. Studies on the regulation of renin genes BA, and Bohm M. Hypercholesterolemia is associated with en-
using transgenic mice. Clin Exp Hypertens 10: 1157–1167, 1988. hanced angiotensin AT1-receptor expression. Am J Physiol Heart
473. Mulrow PJ. The intrarenal renin-angiotensin system. Curr Opin Circ Physiol 272: H2701–H2707, 1997.
Nephrol Hypertens 2: 41– 44, 1993. 495. Nickenig G, Strehlow K, Wassmann S, Baumer AT, Albory K,
474. Mungall BA, Shinkel TA, and Sernia C. Immunocytochemical Sauer H, and Bohm M. Differential effects of estrogen and pro-
localization of angiotensinogen in the fetal and neonatal rat brain. gesterone on AT(1) receptor gene expression in vascular smooth
Neuroscience 67: 505–524, 1995. muscle cells. Circulation 102: 1828 –1833, 2000.
475. Murphy TJ, Alexander RW, Griendling KK, Runge MS, and 496. Nielsen AH, Hagemann A, Avery B, and Poulsen K. Differences
Bernstein KE. Isolation of a cDNA encoding the vascular type-1 in expression of angiotensin II receptors and renin in porcine and
angiotensin II receptor. Nature 351: 233–236, 1991. bovine ovaries. Exp Clin Endocrinol Diabetes 103: 332–338, 1995.

497. Nielsen AH, Hagemann A, and Poulsen K. Effect of gonadotro- 517. Oldner A, Wanecek M, Weitzberg E, Rundgren M, Alving K,
pins and pregnancy on prorenin and renin in the rat. Clin Exp Ullman J, and Rudehill A. Angiotensin II receptor antagonism
Pharmacol Physiol 18: 419 – 424, 1991. increases gut oxygen delivery but fails to improve intestinal muco-
498. Nielsen AH, Winther H, Dantzer V, and Poulsen K. High den- sal acidosis in porcine endotoxin shock. Shock 11: 127–135, 1999.
sities of angiotensin II subtype 2 (AT2) receptors in the porcine 518. Palumbo A, Jones C, Lightman A, Carcangiu ML, DeCherney
placenta and fetal membranes. Placenta 17: 147–153, 1996. AH, and Naftolin F. Immunohistochemical localizaton of renin
499. Nilsson AB, Nitescu N, Chen Y, Guron GS, Marcussen N, and angiotensin II in human ovaries. Am J Obstet Gynecol 160:
Matejka GL, and Friberg P. IGF-I treatment attenuates renal 8 –14, 1989.
abnormalities induced by neonatal ACE inhibition. Am J Physiol 519. Palumbo A, Pourmotabbed G, Carcangiu ML, Andrade-Gor-
Regul Integr Comp Physiol 279: R1050 –R1060, 2000. don P, Roa L, DeCherney A, and Naftolin F. Immunohistochem-
500. Nishii T, Moriguchi A, Morishita R, Yamada K, Nakamura S, ical localization of renin and angiotensin in the ovary: comparison
Tomita N, Kaneda Y, Fukamizu A, Mikami H, Higaki J, and between normal women and patients with histologically proven
Ogihara T. Angiotensinogen gene-activating elements regulate polycystic ovarian disease. Fertil Steril 60: 280 –284, 1993.
blood pressure in the brain. Circ Res 85: 257–263, 1999. 520. Pandey KN, Ascoli M, and Inagami T. Induction of renin activity
501. Nishimura M, Nanbu A, Ohtsuka K, Takahashi H, Iwai N, by gonadotropic hormones in cultured Leydig tumor cells. Endo-
Kinoshita M, and Yoshimura M. Sodium intake regulates renin crinology 117: 2120 –2126, 1985.
gene expression differently in the hypothalamus and kidney of rats. 521. Pandey KN and Inagami T. Regulation of renin angiotensins by
J Hypertens 15: 509 –516, 1997. gonadotropic hormones in cultured murine Leydig tumor cells.
502. Nishimura Y, Ito T, and Saavedra JM. Angiotensin II AT(1) J Biol Chem 261: 3934 –3938, 1986.
blockade normalizes cerebrovascular autoregulation and reduces 522. Pandey KN, Maki M, and Inagami T. Detection of renin mRNA in
cerebral ischemia in spontaneously hypertensive rats. Stroke 31: mouse testis by hybridization with renin cDNA probe. Biochem

2478 –2486, 2000. Biophys Res Commun 125: 662– 667, 1984.
503. Nishimura Y, Xu T, Johren O, Hauser W, and Saavedra JM. 523. Pandey KN, Misono KS, and Inagami T. Evidence for intracel-
The angiotensin AT1 receptor antagonist CV-11974 regulates cere- lular formation of angiotensins: coexistence of renin and angioten-
bral blood flow and brain angiotensin AT1 receptor expression. sin-converting enzyme in Leydig cells of rat testis. Biochem Bio-
Basic Res Cardiol 93 Suppl 2: 63– 68, 1998. phys Res Commun 122: 1337–1343, 1984.
504. Norwood VF, Garmey M, Wolford J, Carey RM, and Gomez 524. Paquet JL, Baudouin-Legros M, Brunelle G, and Meyer P.
RA. Novel expression and regulation of the renin-angiotensin sys- Angiotensin II-induced proliferation of aortic myocytes in sponta-
tem in metanephric organ culture. Am J Physiol Regul Integr neously hypertensive rats. J Hypertens 8: 565–572, 1990.
Comp Physiol 279: R522–R530, 2000. 525. Parmentier M, Inagami T, Pochet R, and Desclin JC. Pituitary-
505. Nouet S and Nahmias C. Signal transduction from the angiotensin
dependent renin-like immunoreactivity in the rat testis. Endo-
II AT2 receptor. Trends Endocrinol Metab 11: 1– 6, 2000.
crinology 112: 1318 –1323, 1983.
506. Nunohiro T, Ashizawa N, Graf K, Do YS, Hsueh WA, and Yano
526. Pastore L, Tessitore A, Martinotti S, Toniato E, Alesse E,
K. Angiotensin II promotes remodelling-related events in cardiac
Bravi MC, Ferri C, Desideri G, Gulino A, and Santucci A.
fibroblasts. Heart Vessels Suppl 12: 201–204, 1997.
Angiotensin II stimulates intercellular adhesion molecule-1
507. Nuyt AM, Lenkei Z, Palkovits M, Corvol P, and Llorens-
(ICAM-1) expression by human vascular endothelial cells and in-
Cortes C. Ontogeny of angiotensin II type 2 receptor mRNA ex-
creases soluble ICAM-1 release in vivo. Circulation 100: 1646 –
pression in fetal and neonatal rat brain. J Comp Neurol 407: 193–
1652, 1999.
206, 1999.
527. Paul M, Bachmann J, and Ganten D. The tissue renin-angioten-
508. Oelkers WK. Effects of estrogens and progestogens on the renin-
aldosterone system and blood pressure. Steroids 61: 166 –171, 1996. sin systems in cardiovascular disease. Trends Cardiovasc Med 2:
509. Ohishi M, Ueda M, Rakugi H, Okamura A, Naruko T, Becker 94 –99, 1992.
AE, Hiwada K, Kamitani A, Kamide K, Higaki J, and Ogihara 528. Paul M, Bader M, Steckelings UM, Voigtländer T, and Ganten
T. Upregulation of angiotensin-converting enzyme during the heal- D. The renin-angiotensin system in the brain: localization and
ing process after injury at the site of percutaneous transluminal functional significance. Arzneim-Forsch Drug Res 43: 207–213,
coronary angioplasty in humans. Circulation 96: 3328 –3337, 1997. 1993.
510. Ohkubo N, Matsubara H, Nozawa Y, Mori Y, Murasawa S, 529. Paul M, Nakamura N, Pratt RE, Burt DW, and Dzau VJ. Cell
Kijiama K, Maruyama K, Masaki K, Tsutumi Y, Shibazaki Y, dependent posttranslational processing and secretion of recombi-
Iwasaka T, and Inada M. Angiotensin type 2 receptors are reex- nant mouse renin-2. Am J Physiol Endocrinol Metab 262: E224 –
pressed in cardiac fibroblasts from failing myopathic hamster E229, 1992.
hearts and inhibit cell growth and fibrillar collagen metabolism. 530. Paul M, Printz MP, Harms E, Unger Th Lang RE, and Ganten
Circulation 96: 3954 –3962, 1997. D. Localization of renin (EC 3.4.2.3) and converting enzyme (EC
511. Ohkubo H, Nakayama K, Tanaka T, and Nakanishi S. Tissue 3.4.1.51) in nerve endings of rat brain. Brain Res 334: 315–324,
distribution of rat angiotensinogen mRNA and structural analysis 1985.
of its heterogeneity. J Biol Chem 261: 319 –323, 1986. 531. Paul M, Wagner D, Metzger R, Ganten D, Lang RE, Suzuki F,
512. Okamura T, Clements DL, and Inagami T. Renin, angiotensins, Murakami K, Burbach JHP, and Ludwig G. Quantification of
and angiotensin converting enzyme in neuroblastoma cell. Evi- renin mRNA in various mouse tissues by a novel solution hybrid-
dence for intracellular formation of angiotensins. Proc Natl Acad ization assay. J Hypertens 6: 247–252, 1988.
Sci USA 78: 6940 – 6943, 1981. 532. Paul M, Wagner J, and Dzau VJ. Gene expression of the compo-
513. Okura T, Kitami Y, Wakamiya R, Marumoto K, Iwata T, and nents of the renin-angiotensin system in human tissues: quantita-
Hiwada K. Renal and extra-renal renin gene expression in spon- tive analysis by the polymerase chain reaction. J Clin Invest 91:
taneously hypertensive rats. Blood Press Suppl 3: 6 –11, 1992. 2058 –2064, 1993.
514. Okuyama A, Nakamura M, Namiki M, Takeyama M, Fujioka H, 534. Paul M, Wagner J, Hoffmann S, Urata H, and Ganten D.
Matsuda M, Matsumoto K, and Sonoda T. Demonstration of Transgenic rats: new experimental models for the study of candi-
gonadotropin-induced plasma renin activity in human internal sper- date genes in hypertension research. Annu Rev Physiol 56: 811–
matic vein. Acta Endocrinol 117: 268 –272, 1988. 829, 1994.
515. Okuyama S, Sakagawa T, Sugiyama F, Fukamizu A, and Mu- 535. Paul M, Zintz M, Böcker W, and Dyer M. Analysis and functional
rakami K. Reduction of depressive-like behavior in mice lacking characterization of the rat endothelin-1 promoter. Hypertension
angiotensinogen. Neurosci Lett 261: 167–170, 1999. 25: 683– 687, 1995.
516. Oldfield BJ, Allen AM, Hards DK, McKinley MJ, Schlawe I, 536. Paul M, Stoll M, Falkenhahn M, and Kreutz R. Cellular local-
and Mendelsohn FA. Distribution of angiotensin II receptor bind- ization of angiotensin converting enzyme gene expression in the
ing in the spinal cord of the sheep. Brain Res 650: 40 – 48, 1994. heart. Basic Res Cardiol 91: 57– 65, 1996.

537. Paul M and Wagner J. Humanized transgenic rats as paradigms in 558. Proudler AJ, Ahmed AI, Crook D, Fogelman I, Rymer JM, and
clinical pharmacology. Can J Physiol Pharmacol 72 Suppl 1: 69, Stevenson JC. Hormone replacement therapy and serum angio-
1994. tensin-converting-enzyme activity in postmenopausal women. Lan-
538. Paul M, Zintz M, Böcker W, and Dyer M. Characterization and cet 346: 89 –90, 1995.
functional analysis of the rat endothelin-1 promoter. Hypertension 559. Pucell AG, Bumpus FM, and Husain A. Rat ovarian angiotensin
25: 683– 687, 1995. II receptors: characterization and coupling to estrogen secretion.
539. Pellicer A, Palumbo A, DeCherney AH, and Naftolin F. Block- J Biol Chem 262: 7076 –7080, 1987.
age of ovulation by an angiotensin antagonist. Science 240: 1660 – 560. Pucell AG, Hodges JC, Sen I, Bumpus FM, and Husain A.
1661, 1988. Biochemical properties of the ovarian granulosa cell type-2-angio-
540. Persson PB, Skalweit A, and Thiele BJ. Controlling the release tensin II receptor. Endocrinology 128: 1947–1959, 1991.
and production of renin. Acta Physiol Scand 181: 375–381, 2004. 561. Qadri F, Edling O, Wolf A, Gohlke P, Culman J, and Unger T.
541. Peters J and Clausmeyer S. Intracellular sorting of renin: cell Release of angiotensin in the paraventricular nucleus in response
type specific differences and their consequences. J Mol Cell Car- to hyperosmotic stimulation in conscious rats: a microdialysis
diol 34: 1561–1568, 2002. study. Brain Res 637: 45– 49, 1994.
542. Peters J, Farrenkopf R, Clausmeyer S, Zimmer J, Kantachu- 562. Quinn SJ and Williams GH. Regulation of aldosterone secretion.
vesiri S, Sharp MG, and Mullins JJ. Functional significance of Annu Rev Physiol 50: 409 – 426, 1988.
prorenin internalization in the rat heart. Circ Res 90: 1135–1141,
563. Quirk WS, Dengerink HA, Coleman JK, and Wright JW. Co-
2002.
chlear blood flow autoregulation in Wistar-Kyoto rats. Hear Res 41:
543. Peterson CM, Morioka N, Zhu C, Ryan JW, and LeMaire WJ.
53– 60, 1989.
Angiotensin-converting enzyme inhibitors have no effect on ovula-
564. Rainey WE, Bird IM, Mason JI, and Carr BR. Angiotensin II
tion and ovarian steroidogenesis in the perfused rat ovary. Reprod
Toxicol 7: 131–135, 1993. receptors on human fetal adrenal cells. Am J Obstet Gynecol 167:

544. Peterson CM, Zhu C, Mukaida T, Butler TA, Woessner JF, and 1679 –1685, 1992.
LeMaire WJ. The angiotensin II antagonist saralasin inhibits ovu- 565. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA,
lation in the perfused rat ovary. Am J Obstet Gynecol 168: 242–245, Griendling KK, and Harrison DG. Angiotensin II-mediated hy-
1993. pertension in the rat increases vascular superoxide production via
545. Petit A, Geoffroy P, and Belisle S. Expression of angiotensin II membrane NADH/NADPH oxidase activation. Contribution to al-
type-I receptor and phospholipase C-linked G alpha q/11 protein in terations of vasomotor tone. J Clin Invest 97: 1916 –1923, 1996.
the human placenta. J Soc Gynecol Invest 3: 316 –321, 1996. 566. Raju GC and Lee YS. Immunohistochemical demonstration of
546. Phillips MI, Speakman EA, and Kimura B. Levels of angiotensin renin in the endometrium. Ann Acad Med Singapore 18: 345–347,
and molecular biology of the tissue renin angiotensin systems. 1989.
Regul Pept 43: 1–20, 1993. 567. Ramaraj P, Kessler SP, Colmenares C, and Sen GC. Selective
547. Phillips MI and Stenstrom B. Angiotensin II in rat brain comi- restoration of male fertility in mice lacking angiotensin-converting
grates with authentic angiotensin II in high pressure liquid chro- enzymes by sperm-specific expression of the testicular isozyme.
motography. Circ Res 56: 212–219, 1985. J Clin Invest 102: 371–378, 1998.
548. Pinto YM, Pinto-Sietsma SJ, Philipp T, Engler S, Kossamehl 568. Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G,
P, Hocher B, Marquardt H, Sethmann S, Lauster R, Merker Lubs HA, Engert S, Stevenson RE, Meindl A, Schwartz CE,
HJ, and Paul M. Reduction in left ventricular messenger RNA for and Nguyen G. A unique exonic splice enhancer mutation in a
transforming growth factor beta(1) attenuates left ventricular fi- family with X-linked mental retardation and epilepsy points to a
brosis and improves survival without lowering blood pressure in novel role of the renin receptor. Hum Mol Genet 14: 1019 –1027,
the hypertensive TGR(mRen2)27 Rat. Hypertension 36: 747–754, 2005.
2000. 569. Rasoul S, Carretero OA, Peng H, Cavasin MA, Zhuo J,
549. Pinto YM, Buikema H, van Gilst WH, Scholtens E, van Geel Sanchez-Mendoza A, Brigstock DR, and Rhaleb NE. Antifi-
PP, de Graeff PA, Wagner J, and Paul M. Cardiovascular end- brotic effect of Ac-SDKP and angiotensin-converting enzyme inhi-
organ damage in Ren-2 transgenic rat compared to spontaneously bition in hypertension. J Hypertens 22: 593– 603, 2004.
hypertensive rats. J Mol Med 75: 371–377, 1997. 570. Reagan LP, Flanagan-Cato LM, Yee DK, Ma LY, Sakai RR, and
550. Plunkett LM, Correa FM, and Saavedra JM. Quantitative auto- Fluharty SJ. Immunohistochemical mapping of angiotensin type 2
radiographic determination of angiotensin-converting enzyme (AT2) receptors in rat brain. Brain Res 662: 45–59, 1994.
binding in rat pituitary and adrenal glands with 125I-351A, a specific 571. Reilly CF, Tewksbury DA, Schechter NM, and Travis J. Rapid
inhibitor. Regul Pept 12: 263–272, 1985. conversion of angiotensin I to angiotensin II by neutrophil and mast
551. Pohlova I and Jelinek J. Components of the renin-angiotensin cell proteinases. J Biol Chem 257: 8619 – 8622, 1982.
system in the rat during development. Pflügers Arch 351: 259 –270, 572. Richoux JP, Bouhnik J, Clauser E, and Corvol P. The renin-
1974.
angiotensin system in the rat brain. Immunocytochemical localiza-
552. Poisner AM, Wood GM, Poisner R, and Inagami T. Renin and
tion of angiotensinogen in glial cells and neurons. Histochemistry
inactive renin in human amnion at term pregnancy. Proc Soc Exp
89: 323–331, 1988.
Biol Med 196: 4 – 6, 1982.
573. Rieger KJ, Saez-Servent N, Papet MP, Wdzieczak-Bakala J,
553. Poisner AM, Wood GW, Poisner R, and Inagami T. Localization
of renin in trophoblasts in human chorion laeve at term pregnancy. Morgat JL, Thierry J, Voelter W, and Lenfant M. Involvement
Endocrinology 109: 1150 –1155, 1981. of human plasma angiotensin I-converting enzyme in the degara-
554. Pokharel S, Rasoul S, Roks AJ, van Leeuwen RE, van Luyn dation of the haemoregulatory peptide N-acetyl seryl aspartyl lysyl
MJ, Deelman LE, Smits JF, Carretero O, van Gilst WH, and proline. Biochem J 270: 3656 –3661, 1993.
Pinto YM. N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of 574. Riva C, Eggli P, Felix D, Mosimann R, and Imboden H. Hypo-
Smad2 in cardiac fibroblasts. Hypertension 40: 155–161, 2002. thalamic accessory nuclei and their relation to the angiotensinergic
555. Pokharel S, van Geel PP, Sharma UC, Cleutjens JP, Bohne- and vasopressinergic systems. Regul Pept 83: 129 –133, 1999.
meier H, Tian XL, Schunkert H, Crijns HJ, Paul M, and Pinto 575. Roberts KA, Krebs LT, Kramar EA, Shaffer MJ, Harding JW,
YM. Increased myocardial collagen content in transgenic rats over- and Wright JW. Autoradiographic identification of brain angioten-
expressing cardiac angiotensin-converting enzyme is related to sin IV binding sites and differential c-Fos expression following
enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased intracerebroventricular injection of angiotensin II and IV in rats.
phosphorylation of Smad2/3. Circulation 110: 3129 –3135, 2004. Brain Res 682: 13–21, 1995.
556. Potter EK. Angiotensin inhibits action of vagus nerve at the heart. 576. Robinson MM, McLennan GP, Thunhorst RL, and Johnson
Br J Pharmacol 75: 9 –11, 1982. AK. Interactions of the systemic and brain renin-angiotensin sys-
557. Poulsen K and Jacobsen J. Inhibition of the enzymatic reaction tems in the control of drinking and the central mediation of pressor
of renin in aggressive mice. J Hypertens 4: 171–180, 1986. responses. Brain Res 842: 55– 61, 1999.

577. Rogers TB, Gaa ST, and Allen IS. Identification and character- as a potential targets for new cardiovascular drugs. Exp Opin
ization of functional angiotensin II receptors on cultured heart Invest Drugs 14: 1019 –1031, 2005.
myocytes. J Pharmacol Exp Ther 236: 438 – 444, 1986. 597. Santos RA, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R,
578. Rogerson FM, Chai SY, Schlawe I, Murray WK, Marley PD, and Campagnole-Santos MJ. Angiotensin-(1O7) and its receptor
and Mendelsohn FAO. Presence of angiotensin converting en- as a potential targets for new cardiovascular drugs. Exp Opin
zyme in the adventitia of large blood vessels. J Hypertens 10: Invest Drugs 14: 1019 –1031, 2005.
615– 620, 1992. 598. Sanvitto GL, Johren O, Hauser W, and Saavedra JM. Water
579. Rogerson FM, Schlawe I, Paxinos G, Chai SY, McKinley MJ, deprivation upregulates ANG II AT1 binding and mRNA in rat
and Mendelsohn FA. Localization of angiotensin converting en- subfornical organ and anterior pituitary. Am J Physiol Endocrinol
zyme by in vitro autoradiography in the rabbit brain. J Chem Metab 273: E156 –E163, 1997.
Neuroanat 8: 227–243, 1995. 599. Sapolsky AI and Woessner JFJ. Multiple forms of cathepsin D
580. Rohmeiss P, Beyer C, Hocher B, Qadri F, Gretz N, Strauch M, from bovine uterus. J Biol Chem 247: 2069 –2076, 1972.
and Unger T. Osmotically induced natriuresis and blood pressure 600. Saridogan E, Djahanbakhch O, Puddefoot JR, Demetroulis C,
response involves angiotensin AT1 receptors in the subfornical Collingwood K, Mehta JG, and Vinson GP. Angiotensin II re-
organ. J Hypertens 13: 1399 –1404, 1995. ceptors and angiotensin II stimulation of ciliary activity in human
581. Rose JM and Audus KL. AT1 receptors mediate angiotensin II fallopian tube. J Clin Endocrinol Metab 81: 2719 –2725, 1996.
uptake and transport by bovine brain microvessel endothelial cells 601. Saris JJ, Derkx FH, de Bruin RJ, Dekkers DH, Lamers JM,
in primary culture. J Cardiovasc Pharmacol 33: 30 –35, 1999. Saxena PR, Schalekamp MA, and Jan Danser AH. High-affinity
582. Rossi GP, Sacchetto A, Cesari M, and Pessina AC. Interactions prorenin binding to cardiac man-6-P/IGF-II receptors precedes pro-
between endothelin-1 and the renin-angiotensin-aldosterone sys- teolytic activation to renin. Am J Physiol Heart Circ Physiol 280:
tem. Cardiovasc Res 43: 300 –307, 1999. H1706 –H1715, 2001.
583. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooper- 602. Saris JJ, Derkx FH, Lamers JM, Saxena PR, Schalekamp MA,

berg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, and Danser AH. Cardiomyocytes bind and activate native human
Johnson KC, Kotchen JM, and Ockene J. Risks and benefits of prorenin: role of soluble mannose 6-phosphate receptors. Hyper-
estrogen plus progestin in healthy postmenopausal women: princi- tension 37: 710 –715, 2001.
pal results from the Women’s Health Initiative randomized con- 603. Saris JJ, van den Eijnden MM, Lamers JM, Saxena PR,
trolled trial. JAMA 288: 321–333, 2002. Schalekamp MA, and Danser AH. Prorenin-induced myocyte
584. Rothermund L, Kreutz R, Kossmehl P, Fredersdorf S, proliferation: no role for intracellular angiotensin II. Hypertension
Shakibaei M, Schulze-Tanzol G, Paul M, and Grimm D. Early 39: 573–577, 2002.
onset of chondroitin sulfate and osteopontin expression in angio- 604. Sayeski PP and Bernstein KE. Signal transduction mechanisms
tensin II dependent left ventricular hypertrophy. Am J Hypertens of the angiotensin II type AT(1)-receptor: looking beyond the het-
15: 644 – 652, 2002. erotrimeric G protein paradigm. J Renin Angiotensin Aldosterone
585. Rothermund L, Pinto YM, Hocher B, Vetter R, Leggewie S, Syst 2: 4 –10, 2001.
Kobetamehl P, Orzechowski HD, Kreutz R, and Paul M. Car- 605. Schauser KH, Nielsen AH, Winther H, Dantzer V, and Poulsen
diac endothelin system impairs left ventricular function in renin- K. Autoradiographic localization and characterization of angioten-
dependent hypertension via decreased sarcoplasmic reticulum sin II receptors in the bovine placenta and fetal membranes. Biol
Ca2⫹ uptake. Circulation 102: 1582–1588, 2000. Reprod 59: 684 – 692, 1998.
586. Rothermund L, Pinto YM, Vetter R, Herfort N, Kossmehl P, 606. Schelling P, Fischer H, and Ganten D. Angiotensin and cell
Neumayer HH, Paul M, and Kreutz R. Effects of angiotensin II growth: a link to cardiovascular hypertrophy? J Hypertens 9: 3–15,
subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic 1991.
reticulum Ca2⫹ handling in hypertensive transgenic rats overex- 607. Schelling P, Ganten D, Speck G, and Fischer H. Effects of
pressing the Ren2 gene. J Hypertens 19: 1465–1472, 2001. angiotensin II and angiotensin II antagonist saralasin on cell
587. Sadoshima J, Xu Y, Slayter H, and Izumo S. Autocrine release growth and renin in 3T3 and SV3T3 cells. J Cell Physiol 98: 503–513,
of angiotensin II mediates stretch-induced hypertrophy of cardiac 1979.
myocytes in vitro. Cell 75: 977–984, 1993. 608. Schelling P, Ganten D, Speck G, and Fischer H. Effects of
588. Safonova I, Aubert J, Negrel R, and Ailhaud G. Regulation by angiotensin II and angiotensin II antagonist saralasin on cell
fatty acids of angiotensinogen gene expression in preadipose cells. growth and renin in 3T3 and SV3T3 cells. J Cell Physiol 98: 503–514,
Biochem J 322: 235–239, 1997. 1979.
589. Sahin Y, Kontas O, Muderris II, and Cankurtaran M. Effects of 609. Schelling P, Ganten U, Sponer G, Unger Th, and Ganten D.
angiotensin converting enzyme inhibitor cilazapril and angiotensin Components of the renin-angiotensin system in the cerebrospinal
II antagonist saralasin in ovarian hyperstimulation syndrome in the fluid of rats and dogs with special consideration of the origin and
rabbit. Gynecol Endocrinol 11: 231–236, 1997. the fate of angiotensin II. Neuroendocrinology 31: 297–308, 1980.
590. Saito K, Gutkind JS, and Saavedra JM. Angiotensin II binding 610. Schelling P, Hutchinson JS, Ganten U, Sponer G, and Ganten
sites in the conduction system of rat hearts. Am J Physiol Heart D. Impermeability of the blood-cerebrospinal fluid barrier for an-
Circ Physiol 253: H1618 –H1622, 1987. giotensin II in rats. Clin Sci Mol Med 51: 399s– 402s, 1976.
591. Sakagawa T, Okuyama S, Kawashima N, Hozumi S, Nakaga- 611. Schelling P, Meyer D, Loos HE, Speck G, Phillips MI, Johnson
wasai O, Tadano T, Kisara K, Ichiki T, and Inagami T. Pain AK, and Ganten D. A micromethod for the measurement of renin
threshold, learning and formation of brain edema in mice lacking in brain nuclei: its application in spontaneously hypertensive rats.
the angiotensin II type 2 receptor. Life Sci 67: 2577–2585, 2000. Neuropharmacology 21: 435– 463, 1982.
592. Sakai K and Sigmund CD. Molecular evidence of tissue renin- 612. Schiavone MT, Khosla MC, and Ferrario CM. Angiotensin-
angiotensin systems: a focus on the brain. Curr Hypertens Rep 7: [1O7]: evidence for novel actions in the brain. J Cardiovasc Phar-
135–140, 2005. macol 16 Suppl 4: S19 –S24, 1990.
593. Sakamoto S, Obayashi S, Aso T, Sato J, Hamasaki H, and 613. Schieffer B, Drexler H, Ling BN, and Marrero MB. G protein-
Azuma H. The mechanism of myometrial contractions induced by coupled receptors control vascular smooth muscle cell prolifera-
endothelin-1 in rat. Mol Hum Reprod 3: 1029 –1035, 1997. tion via pp60c-src and p21ras. Am J Physiol Cell Physiol 272:
594. Samani NJ, Morgan K, Brammar WJ, and Swales JD. Detection C2019 –C2030, 1997.
of renin messenger RNA in rat tissues: increased sensitivity using 614. Schiffrin EL. Vascular endothelin in hypertension. Vasc Pharma-
an RNAse protection technique. J Hypertens 5 Suppl 2: S19 –S21, col 43: 19 –29, 2005.
1987. 615. Schiller PW, Demassieux S, and Boucher R. Substrate specific-
595. Santos RA, Campagnole-Santos MJ, and Andrade SP. Angio- ity of tonin from rat submaxillary gland. Circ Res 39: 629 – 632,
tensin-(1O7): an update. Regul Pept 91: 45– 62, 2000. 1976.
596. Santos RA, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R, 616. Schinke M, Baltatu O, Bohm M, Peters J, Rascher W, Bricca G,
and Campagnole-Santos MJ. Angiotensin-(1O7) and its receptor Lippoldt A, Ganten D, and Bader M. Blood pressure reduction

and diabetes insipidus in transgenic rats deficient in brain angio- 637. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, and
tensinogen. Proc Natl Acad Sci USA 96: 3975–3980, 1999. Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase
617. Schinke M, Doods HN, and Entzeroth M. Characterization of the activity: upstream mediators. Circ Res 91: 406 – 413, 2002.
angiotensin II receptor subtype in rat ileum. Naunyn-Schmiede- 638. Shah DM. Role of the renin-angiotensin system in the pathogenesis
berg’s Arch Pharmacol 343: 282, 1991. of preeclampsia. Am J Physiol Renal Physiol 288: F614 –F625,
618. Schinke M, Doods HN, Ganten D, Wienen W, and Entzeroth 2005.
M. Characterization of rat intestinal angiotensin II receptors. Eur 639. Shanmugam S, Corvol P, and Gasc JM. Ontogeny of the two
J Pharmacol 204: 165–170, 1991. angiotensin II type 1 receptor subtypes in rats. Am J Physiol
619. Schirar A, Capponi A, and Catt KJ. Regulation of uterine angio- Endocrinol Metab 267: E828 –E836, 1994.
tensin II receptors by estrogen and progesterone. Endocrinology 640. Shapiro MS, Wollmuth LP, and Hille B. Angiotensin II inhibits
106: 5–12, 1980. calcium and M current channels in rat sympathetic neurons via G
620. Schling P, Mallow H, Trindl A, and Loffler G. Evidence for a proteins. Neuron 12: 1319 –1329, 1994.
local renin angiotensin system in primary cultured human preadi- 641. Shaw KJ, Do YS, Kjos S, Anderson PW, Shinagawa T, Dubeau
pocytes. Int J Obes Relat Metab Disord 23: 336 –341, 1999. L, and Hsueh WA. Human decidua is a major source of renin.
621. Schmitz C, Gotthardt M, Hinderlich S, Leheste JR, Gross V, J Clin Invest 83: 2085–2092, 1989.
Vorum H, Christensen EI, Luft FC, Takahashi S, and Willnow 642. Shelat SG, Reagan LP, King JL, Fluharty SJ, and Flanagan-
TE. Normal blood pressure and plasma renin activity in mice Cato LM. Analysis of angiotensin type 2 receptors in vasopressin-
lacking the renin-binding protein, a cellular renin inhibitor. J Biol ergic neurons and pituitary in the rat. Regul Pept 73: 103–112, 1998.
Chem 275: 15357–15362, 2000. 643. Shenoy U and Cassis L. Characterization of renin activity in
622. Schuijt MP, Basdew M, van VR, de VR, Saxena PR, Schoe- brown adipose tissue. Am J Physiol Cell Physiol 272: C989 –C999,
maker RG, and Danser AH. AT(2) receptor-mediated vasodila- 1997.
tion in the heart: effect of myocardial infarction. Am J Physiol 644. Shenoy UV, Richards EM, Huang XC, and Sumners C. Angio-

Heart Circ Physiol 281: H2590 –H2596, 2001. tensin II type 2 receptor-mediated apoptosis of cultured neurons
623. Schulman IH, Zhou MS, and Raij L. Nitric oxide, angiotensin II, from newborn rat brain. Endocrinology 140: 500 –509, 1999.
and reactive oxygen species in hypertension and atherogenesis. 645. Shibata K, Makino I, Shibaguchi H, Niwa M, Katsuragi T, and
Curr Hypertens Rep 7: 61– 67, 2005. Furukawa T. Up-regulation of angiotensin type 2 receptor mRNA
624. Schultze D, Brunswig B, and Mukhopadhyay AK. Renin and by angiotensin II in rat cortical cells. Biochem Biophys Res Com-
prorenin-like activities in bovine ovarian follicles. Endocrinology mun 239: 633– 637, 1997.
124: 1389 –1398, 1989. 646. Shibuya K, Kanasaki K, Isono M, Sato H, Omata M, Sugimoto
625. Schunkert H, Danser AH, Hense HW, Derkx FH, Kurzinger S, T, Araki S, Isshiki K, Kashiwagi A, Haneda M, and Koya D.
and Riegger GA. Effects of estrogen replacement therapy on the N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency
renin-angiotensin system in postmenopausal women. Circulation and mesangial matrix expansion in diabetic db/db mice. Diabetes
95: 39 – 45, 1997. 54: 838 – 845, 2005.
626. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, and 647. Shimada K and Yazaki Y. Binding sites for angiotensin II in
Lorell BH. Increased rat cardiac angiotensin converting enzyme human mononuclear leucocytes. J Biochem 84: 1013–1015, 1978.
activity and mRNA expression in pressure overload left ventricular 648. Shimoike H, Iwai N, and Kinoshita M. Genetic analysis of renin
hypertrophy. J Clin Invest 86: 1913–1920, 1990. gene expression in the central nervous system of spontaneously
627. Schunkert H, Ingelfinger JR, and Dzau VJ. Evolving concepts hypertensive rats. Neurosci Lett 221: 133–136, 1997.
of the intrarenal renin-angiotensin system in health and disease: 649. Shinagawa K, Derakhchan K, and Nattel S. Pharmacological
contributions of molecular biology. Renal Physiol Biochem 14: prevention of atrial tachycardia induced atrial remodeling as a
146 –154, 1991. potential therapeutic strategy. Pacing Clin Electrophysiol 26: 752–
628. Schunkert H, Ingelfinger JR, Hirsch AT, Pinto Y, Remme WJ, 764, 2003.
Jacob H, and Dzau VJ. Feedback regulation of angiotensin con- 650. Shiratori Y, Nakagawa S, Hori H, Murakami K, and Umeyama
verting enzyme activity and mRNA levels by angiotensin II. Circ H. Protein modeling of human prorenin using the molecular dy-
Res 72: 312–318, 1993. namics method. J Mol Graph 8: 163–167, 1990.
629. Schunkert H, Jackson B, Tang SS, Schoen FJ, Smits JFM, 651. Siegel SR and Fisher DA. Ontogeny of the renin-angiotensin-
Apstein CS, and Lorell BH. Distribution and functional relevance aldosterone system in the fetal and newborn lamb. Pediatr Res 14:
of cardiac angiotensin converting enzyme in hypertrophied rat 99 –102, 1980.
hearts. Circulation 87: 1328 –1339, 1993. 652. Sigmund CD. Genetic manipulation of the renin-angiotensin sys-
630. Schutz S, Le Moullec JM, Corvol P, and Gasc JM. Early ex- tem: targeted expression of the renin-angiotensin system in the
pression of all the components of the renin-angiotensin-system in kidney. Am J Hypertens 14: 33S–37S, 2001.
human development. Am J Pathol 149: 2067–2079, 1996. 653. Sigmund CD, Jones CA, Mullins JJ, Kim U, and Gross KW.
631. Sealey JE, White RP, Laragh JH, and Rubin AL. Plasma prore- Expression of murine renin genes in subcutaneous connective
nin and renin in anephric patients. Circ Res 41: 17–21, 1977. tissue. Proc Natl Acad Sci USA 87: 7993–7997, 1990.
632. Sealey JE, Wilson M, Morganti AA, Zervoudakis I, and Laragh 654. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U,
JH. Changes in active and inactive renin throughout normal preg- Herzlinger D, and Levi R. Mast cells: a unique source of renin.
nancy. Clin Exp Hypertens 4: 2373–2384, 1982. Proc Natl Acad Sci USA 101: 13607–13612, 2004.
633. Sechi LA, Valentin JP, Griffin CA, and Schambelan M. Auto- 655. Silvestre JS, Tamarat R, Senbonmatsu T, Icchiki T, Ebrahim-
radiographic characterization of angiotensin II receptor subtypes ian T, Iglarz M, Besnard S, Duriez M, Inagami T, and Levy BI.
in rat intestine. Am J Physiol Gastrointest Liver Physiol 265: Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-
G21–G27, 1993. induced angiogenesis in mice hindlimb. Circ Res 90: 1072–1079,
634. Seely EW, Brosnihan KB, Jeunemaitre X, Okamura K, Wil- 2002.
liams GH, Hollenberg NK, and Herrington DM. Effects of con- 656. Sim MK and Seng KM. Development of angiotensin converting
jugated oestrogen and droloxifene on the renin-angiotensin system, enzyme in fetal lung and placenta of the rat and human. Clin Exp
blood pressure and renal blood flow in postmenopausal women. Pharmacol Physiol 11: 497–501, 1984.
Clin Endocrinol 60: 315–321, 2004. 657. Simon MR, Kamlay MT, Khan M, and Melmon K. Angiotensin II
635. Senbonmatsu T, Ichihara S, Price E Jr, Gaffney FA, and binding to human mononuclear cells. Immunopharmacol Immu-
Inagami T. Evidence for angiotensin II type 2 receptor-mediated notoxicol 11: 63– 80, 1989.
cardiac myocyte enlargement during in vivo pressure overload. 658. Singh US, Kumar MV, and Panda JN. Angiotensin converting
J Clin Invest 106: R25–R29, 2000. enzyme in semen and its possible role in capacitation. Andrologia
636. Seo MS, Fukamizu A, Saito T, and Murakami K. Identification 17: 472– 475, 1985.
of a previously unrecognized production site of human renin. Bio- 659. Skinner SL, Cran EJ, Gibson R, Taylor R, Walters WA, and
chim Biophys Acta 1129: 87– 89, 1991. Catt KJ. Angiotensins I and II, active and inactive renin, renin

substrate, renin activity, and angiotensinase in human liquor amnii proliferation in coronary endothelial cells. J Clin Invest 95: 651–
and plasma. Am J Obstet Gynecol 121: 626 – 630, 1975. 657, 1995.
660. Skinner SL, Lumbers ER, and Symonds EM. Renin concentra- 682. Strain WD and Chaturvedi N. The renin-angiotensin-aldosterone
tion in human fetal and maternal tissues. Am J Obstet Gynecol 101: system and the eye in diabetes. J Renin Angiotensin Aldosterone
529 –533, 1968. Syst 3: 243–246, 2002.
661. Smith RD. Characterisation of AT1 angiotensin receptors on cul- 683. Strittmatter SM, Lo MMS, Javitch JA, and Snyder SH. Auto-
tured rat intestinal epithelial (RIE-1) cells. Biochem Mol Biol Int 32: radiographic visualization of angiotensin-converting enzyme in rat
923–931, 1994. brain with [3H]captopril: localization to a striatonigral pathway.
662. Song K, Allen AM, Paxinos G, and Mendelsohn FA. Mapping of Proc Natl Acad Sci USA 81: 1599 –1603, 1984.
angiotensin II receptor subtype heterogeneity in rat brain. J Comp 684. Strittmatter SM and Snyder SH. Angiotensin-converting enzyme
Neurol 316: 467– 484, 1992. in the male rat reproductive system: autoradiographic visualization
663. Sood PP, Richoux JP, Panigel M, Bouhnik J, and Wegmann R. with [3H]captopril. Endocrinology 115: 2332–2341, 1984.
Differential distribution of immunoreactive angiotensinogen in the 685. Sun Y, Diaz-Arias AA, and Weber KT. Angiotensin-converting
hind-brain and spinal cord of neonatal and adult rats. Acta Anat enzyme, bradykinin, and angiotensin II receptor binding in rat skin,
138: 230 –237, 1990. tendon, and heart valves: an in vitro, quantitative autoradiographic
664. Soubrier F, Hubert C, Testut P, Nadaud S, Alhenc-Gelas F, study. J Lab Clin Med 123: 372–377, 1994.
and Corvol P. Molecular biology of the angiotensin I converting 686. Sun Y, Ramires FJ, Zhou G, Ganjam VK, and Weber KT.
enzyme. I. Biochemistry and structure of the gene. J Hypertens 11: Fibrous tissue and angiotensin II. J Mol Cell Cardiol 29: 2001–2012,
471– 476, 1993. 1997.
665. Soubrier F, Wei L, Hubert C, Clauser E, Alhenc-Gelas F, and 687. Sun Y and Weber KT. Angiotensin-converting enzyme and wound
Corvol P. Molecular biology of the angiotensin I converting en- healing in diverse tissues of the rat. J Lab Clin Med 127: 94 –101,

zyme. II. Structure-function. Gene polymorphism and clinical im- 1996.
plications. J Hypertens 11: 599 – 604, 1993. 688. Suter C and Coote JH. Intrathecally administered angiotensin II
666. Speck G, Poulsen K, Unger Th Rettig R, Bayer C, Schölkens B, increases sympathetic activity in the rat. J Auton Nerv Syst 19:
and Ganten D. In vivo activity of purified mouse brain renin. 31–37, 1987.
Brain Res 219: 371–384, 1981. 689. Suzuki F, Hayakawa M, Nakagawa T, Nasir UM, Ebihara A,
667. Speth RC, Bumpus FM, and Husain A. Identification of angio- Iwasawa A, Ishida Y, Nakamura Y, and Murakami K. Human
tensin II receptors in the rat ovary. Eur J Pharmacol 130: 351–352, prorenin has “gate and handle” regions for its non-proteolytic ac-
1986. tivation. J Biol Chem 278: 22217–22222, 2003.
668. Speth RC, Daubert DL, and Grove KL. Angiotensin II: a repro- 690. Suzuki Y, Erickson RH, Sedlmayer A, Chang SK, Ikehara Y,
ductive hormone too? Regul Pept 79: 25– 40, 1999. and Kim YS. Dietary regulation of rat intestinal angiotensin-con-
669. Speth RC and Husain A. Distribution of angiotensin-converting verting enzyme and dipeptidyl peptidase IV. Am J Physiol Gastro-
enzyme and angiotensin II-receptor binding sites in the rat ovary. intest Liver Physiol 264: G1153–G1159, 1993.
Biol Reprod 38: 695–702, 1988. 691. Swanson GN, Hanesworth JM, Sardinia MF, Coleman JK,
670. Sramek SJ, Wallow IH, Tewksbury DA, Brandt CR, and Wright JW, Hall KL, Miller-Wing AV, Stobb JW, Cook VI, and
Poulsen GL. An ocular renin-angiotensin system. Immunohisto- Harding EC. Discovery of a distinct binding site for angiotensin II
chemistry of angiotensinogen. Invest Ophthalmol Vis Sci 33: 1627– (3O8), a putative angiotensin IV receptor. Regul Pept 40: 409 – 419,
1632, 1992. 1992.
671. Sramek SJ, Wallow IHL, Day RP, and Ehrlich EN. Ocular 692. Tada M, Fukamizu A, Seo MS, Takahashi S, and Murakami K.
renin-angiotensin: immunohistochemical evidence for the presence Renin expression in the kidney and brain is reciprocally controlled
of prorenin in eye tissue. Invest Ophthalmol Vis Sci 29: 1749 –1752, by captopril. Biochem Biophys Res Commun 159: 1065–1071, 1989.
1988. 693. Tada M, Takahashi S, Miyano M, and Miyake Y. Tissue-specific
672. Stalcup SA, Pang LM, Lipset JS, Odya CE, Goodfriend TL, regulation of renin-binding protein gene expression in rats. J Bio-
and Mellins RB. Gestational changes in pulmonary converting chem 112: 175–182, 1992.
enzyme activity in the fetal rabbit. Circ Res 43: 705–711, 1978. 694. Tadros T, Traber DL, Heggers JP, and Herndon DN. Angioten-
673. Steckelings UM, Artuc M, Paul M, Stoll M, and Henz BM. sin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut
Angiotensin II stimulates proliferation of primary human keratino- ischemia, lipid peroxidation, mucosal permeability, and bacterial
cytes via a non-AT1, non-AT2 angiotensin receptor. Biochem Bio- translocation. Ann Surg 231: 566 –576, 2000.
phys Res Commun 229: 329 –333, 1996. 695. Tahmasebi M, Puddefoot JR, Inwang ER, and Vinson GP. The
674. Steckelings UM, Bottari SP, Stoll M, Wagner J, and Unger T. tissue renin-angiotensin system in human pancreas. J Endocrinol
Repression of c-fos and c-jun gene expression is not part of AT2 161: 317–322, 1999.
receptor coupled signal transduction. J Mol Med 76: 202–207, 1998. 696. Takahashi N and Smithies O. Gene targeting approaches to
675. Steckelings UM and Czarnetzki BM. The renin-angiotensin-sys- analyzing hypertension. J Am Soc Nephrol 10: 1598 –1605, 1999.
tem in the skin. Evidence for its presence and possible functional 697. Takahashi S, Inoue H, and Miyake Y. The human gene for
implications. Exp Dermatol 4: 329 –334, 1995. renin-binding protein. J Biol Chem 267: 13007–13013, 1992.
676. Steckelings UM, Kaschina E, and Unger T. The AT2 receptor: a 698. Takahashi S, Ohsawa T, Miura R, and Miyake Y. Purification of
matter of love and hate. Peptides 26: 1401–1409, 2005. high molecular weight (HMW) renin from porcine kidney and di-
677. Steele MK, Gallo RV, and Ganong WF. A possible role for the rect evidence that the HMW renin is a complex of renin with renin
brain renin-angiotensin system in the regulation of LH secretion. binding protein (RnBP). J Biochem 93: 265–274, 1983.
Am J Physiol Regul Integr Comp Physiol 245: R805–R810, 1983. 699. Takahashi S, Takahashi K, Kaneko T, Ogasawara H, Shindo S,
678. Stevens BR, Fernandez A, Kneer C, Cerda JJ, Phillips MI, and and Kobayashi M. Human renin-binding protein is the enzyme
Woodward ER. Human intestinal brush border angiotensin-con- N-acetyl-D-glucosamine 2-epimerase. J Biochem 125: 348 –353,
verting enzyme activity and its inhibition by antihypertensive 1999.
ramipril. Gastroenterology 94: 942–947, 1988. 700. Takai S, Jin D, Muramatsu M, Okamoto Y, and Miyazaki M.
679. Stevens BR, Fernandez A, and Martinez DR. Angiotensin con- Therapeutic applications of chymase inhibitors in cardiovascular
verting enzyme in brush-border membranes of avian small intes- diseases and fibrosis. Eur J Pharmacol 501: 1– 8, 2004.
tine. J Exp Biol 135: 1– 8, 1988. 701. Tamura K, Tanimoto K, Takahashi S, Sagara M, Fukamizu A,
680. Stoll M, Meffert S, Stroth U, and Unger T. Growth or anti- and Murakami K. Structure and expression of the mouse angio-
growth: angiotensin and the endothelium. J Hypertens 13: 1529 – tensinogen gene. Jpn Heart J 33: 113–124, 1992.
1534, 1995. 702. Tan LB, Jalil JE, Pick R, Janicki JS, and Weber KT. Cardiac
681. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, and myocyte necrosis induced by angiotensin II. Circ Res 69: 1185–
Unger T. The angiotensin AT2-receptor mediates inhibition of cell 1195, 1991.

703. Tanaka J, Hori K, and Nomura M. Diminished salt appetite in 723. Tsutsumi K, Viswanathan M, Strömberg C, and Saavedra JM.
spontaneously hypertensive rats following local administration of Type-1 and type-2 angiotensin II receptors in fetal rat brain. Eur
the angiotensin II antagonist saralasin in the median preoptic area. J Pharmacol 198: 89 –92, 1991.
Behav Pharmacol 8: 752–756, 1997. 724. Unger T. The angiotensin type 2 receptor: variations on an enig-
704. Tang SS, Rogg H, Schumacher R, and Dzau VJ. Characterization matic theme. J Hypertens 17: 1775–1786, 1999.
of nuclear angiotensin-II-binding sites in rat liver and comparison 725. Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P,
with plasma membrane receptors. Endocrinology 131: 374 –380, Hohle S, Meffert S, Stoll M, Stroth U, and Zhu YZ. Angiotensin
1992. receptors. J Hypertens Suppl 14: S95–S103, 1996.
705. Tasker AS, Sorensen BK, Jae HS, Winn M, von Geldern TW, 726. Unger T, Ganten D, and Lang RE. Tissue converting enzyme and
Dixon DB, Chiou WJ, Dayton BD, Calzadila S, Hernandez L, cardiovascular actions of converting enzyme inhibitors. J Cardio-
Marsh KC, WuWong JR, and Opgenorth TJ. Potent and selec- vasc Pharmacol 8 Suppl 10: S75–S81, 1986.
tive non-benzodioxole-containing endothelin-A receptor antago- 727. Unger T, Gohlke P, Paul M, and Rettig R. Tissue renin-angio-
nists. J Med Chem 40: 322–330, 1997. tensin systems: fact or fiction? J Cardiovasc Pharmacol 18 Suppl 2:
706. Tea BS, Der SS, Touyz RM, Hamet P, and deBlois D. Proapo- S20 –S25, 1991.
ptotic and growth-inhibitory role of angiotensin II type 2 receptor 728. Urata H, Nishimura H, and Ganten D. Chymase-dependent an-
in vascular smooth muscle cells of spontaneously hypertensive rats giotensin II forming systems in humans. Am J Hypertens 9: 277–
in vivo. Hypertension 35: 1069 –1073, 2000. 284, 1996.
707. Thekkumkara TJ, Livingstone WI, Kumar RS, and Sen GC. 729. Urata H, Healy B, Stewart RW, Bumpus FM, and Husain A.
Use of alternative polyadenylation sites for tissue-specific tran- Angiotensin II-forming pathways in normal and failing human
scription of two angiotensin-converting enzyme mRNAs. Nucleic hearts. Circ Res 66: 883– 890, 1990.
Acids Res 20: 683– 687, 1992. 730. Urata H, Kinoshita A, Perez DM, Misono KS, Bumpus FM,
Graham RM, and Husain A. Cloning of the gene and cDNA for

708. Thomas DW and Hoffman MD. Identification of macrophage
receptors for angiotensin: a potential role in antigen uptake for T human heart chymace. J Biol Chem 266: 17173–17179, 1991.
lymphocyte responses? J Immunol 132: 2807–2812, 1984. 731. Urata H, Strobel F, and Ganten D. Widespread tissue distribu-
709. Thomas WG, Greenland KJ, Shinkel TA, and Sernia C. Angio- tion of human chymase. J Hypertens Suppl 12: S17–S22, 1994.
tensinogen is secreted by pure rat neuronal cell cultures. Brain Res 732. Van HV, Ariapart P, Hoffstedt J, Lundkvist I, Bringman S, and
588: 191–200, 1992. Arner P. Increased adipose angiotensinogen gene expression in
710. Thomas WG and Sernia C. The immunocytochemical localization human obesity. Obes Res 8: 337–341, 2000.
of angiotensinogen in the rat ovary. Cell Tissue Res 261: 367–373, 733. Van den Eijnden MM, Saris JJ, de Bruin RJ, De WE, Sluiter W,
1990. Reudelhuber TL, Schalekamp MA, Derkx FH, and Danser AH.
711. Tian XL, Pinto YM, Costerousse O, Franz WM, Lippoldt A, Prorenin accumulation and activation in human endothelial cells:
Hoffmann S, Unger T, and Paul M. Over-expression of angioten- importance of mannose 6-phosphate receptors. Arterioscler
sin converting enzyme-1 augments cardiac hypertrophy in trans- Thromb Vasc Biol 21: 911–916, 2001.
734. Van der Meer P, Lipsic E, Westenbrink BD, van de Wal RM,
genic rats. Hum Mol Genet 13: 1441–1450, 2004.
Schoemaker RG, Vellenga E, van Veldhuisen DJ, Voors AA,
712. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P,
and van Gilst WH. Levels of hematopoiesis inhibitor N-acetyl-
Carini DJ, Lee RJ, Wexler RR, Saye JA, and Smith RD. Angio-
seryl-aspartyl-lysyl-proline partially explain the occurrence of ane-
tensin II receptors and angiotensin II receptor antagonists. Phar-
mia in heart failure. Circulation 112: 1743–1747, 2005.
macol Rev 45: 205–251, 1993.
735. Vanha-Perttula T, Mather JP, Bardin CW, Moss SB, and
713. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, and
Bellve AR. Localization of the antigotensin-converting enzyme
Turner AJ. A human homolog of angiotensin-converting enzyme.
activity in testis and epididymis. Biol Reprod 33: 870 – 877, 1985.
Cloning and functional expression as a captopril-insensitive car-
736. Van Kats JP, Danser AH, van Meegen J, Verdouw PD, and
boxypeptidase. J Biol Chem 275: 33238 –33243, 2000. Schalekamp MA. Angiotensin production by the heart: a quanti-
714. Touyz RM and Schiffrin EL. Increased generation of superoxide tative study in pigs with the use of radiolabeled angiotensin infu-
by angiotensin II in smooth muscle cells from resistance arteries of sions. Circulation 98: 73– 81, 1998.
hypertensive patients: role of phospholipase D-dependent 737. Van Kesteren CA, Danser AH, Derkx FH, Dekkers DH, Lam-
NAD(P)H oxidase-sensitive pathways. J Hypertens 19: 1245–1254, ers JM, Saxena PR, and Schalekamp MA. Mannose 6-phosphate
2001. receptor-mediated internalization and activation of prorenin by
715. Troffa C, Tonolo G, Melis MG, Manunta P, Soro A, Pala F, cardiac cells. Hypertension 30: 1389 –1396, 1997.
Pazzola A, Sabino G, Masala A, and Maioli M. Effect of angio- 738. Van Kesteren CA, van Heugten HA, Lamers JM, Saxena PR,
tensin converting enzyme inhibition on the menstrual cycle of Schalekamp MA, and Danser AH. Angiotensin II-mediated
hypertensive women. J Cardiovasc Pharmacol 18: 462– 467, 1991. growth and antigrowth effects in cultured neonatal rat cardiac
716. Tsuchihashi T, Kagiyama S, Matsumura K, Lin Y, Abe I, and myocytes and fibroblasts. J Mol Cell Cardiol 29: 2147–2157, 1997.
Fujishima M. Cardiovascular responses to glutamate and angio- 739. Van Sande M, Inokuchi J, Nagamatsu A, Scharpe S, Neels H,
tensin II in ventrolateral medulla of hypertension induced by and Van Camp K. Tripeptidyl carboxypeptidase activity of angio-
chronic inhibition of nitric oxide. Hypertens Res 23: 359 –364, 2000. tensin-converting enzyme in human tissues of the urogenital tract.
717. Tsutsumi K and Saavedra JM. Quantitative autoradiography re- Urol Int 40: 100 –102, 1985.
veals different angiotensin II receptor subtypes in selected rat brain 740. Veniant M, Menard J, Bruneval P, Morley S, Gonzales MF,
nuclei. J Neurochem 56: 348 –351, 1991. and Mullins JJ. Vascular damage without hypertension in trans-
718. Tsutsumi K and Saavedra JM. Heterogeneity of angiotensin II genic rats expressing prorenin exclusively in the liver. J Clin Invest
AT2 receptors in the rat brain. Mol Pharmacol 41: 290 –297, 1991. 98: 1966 –1970, 1996.
719. Tsutsumi K and Saavedra JM. Characterization of AT2 angioten- 741. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J,
sin II receptors in rat anterior cerebral arteries. Am J Physiol Heart Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane
Circ Physiol 261: H667–H670, 1991. M, Nichols A, and Tummino P. Hydrolysis of biological peptides
720. Tsutsumi K and Saavedra JM. Characterization and develop- by human angiotensin-converting enzyme-related carboxypepti-
ment of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. dase. J Biol Chem 277: 14838 –14843, 2002.
Am J Physiol Regul Integr Comp Physiol 261: R209 –R216, 1991. 742. Vila-Porcile E and Corvol P. Angiotensinogen, prorenin, and
721. Tsutsumi K, Seltzer A, and Saavedra JM. Angiotensin II recep- renin are co-localized in the secretory granules of all glandular cells
tor subtypes and angiotensin-converting enzyme in the fetal rat of the rat anterior pituitary: an immunoultrastructural study. J His-
brain. Brain Res 631: 212–220, 1993. tochem Cytochem 46: 301–311, 1998.
722. Tsutsumi K, Stromberg C, and Saavedra JM. Characterization 743. Vinson GP, Puddefoot JR, Ho MM, Barker S, Mehta J, Sari-
of angiotensin II receptor subtypes in the rat spleen. Peptides 13: dogan E, and Djahanbakhch O. Type 1 angiotensin II receptors in
291–296, 1992. rat and human sperm. J Endocrinol 144: 369 –378, 1995.

744. Vio CP and Jeanneret VA. Local induction of angiotensin-con- 765. Warren AY, Craven DJ, and Symonds EM. Production of active
verting enzyme in the kidney as a mechanism of progressive renal and inactive renin by cultured explants from the human female
diseases. Kidney Int 86 Suppl: S57–S63, 2003. genital tract. Br J Obstet Gynaecol 89: 628 – 632, 1982.
745. Viswanathan M and Saavedra JM. Expression of angiotensin II 766. Watanabe T, Hashimoto M, Okuyama S, Inagami T, and Na-
AT2 receptors in the rat skin during experimental wound healing. kamura S. Effects of targeted disruption of the mouse angiotensin
Peptides 13: 783–786, 1992. II type 2 receptor gene on stress-induced hyperthermia. J Physiol
746. Voigt JP, Hortnagl H, Rex A, van HL, Bader M, and Fink H. 515: 881– 885, 1999.
Brain angiotensin and anxiety-related behavior: the transgenic rat 767. Wei L, Alhenc-Gelas F, Soubrier F, Michaud A, Corvol P, and
TGR(ASrAOGEN)680. Brain Res 1046: 145–156, 2005. Clauser E. Expression and characterization of recombinant hu-
747. Volicer L and Loew CG. Penetration of angiotensin II into the man angiotensin I-converting enzyme. Evidence for a C-terminal
brain. Neuropharmacology 10: 631– 636, 1971. transmembrane anchor and for a proteolytic processing of the
748. Von Bohlen und Hahlbach O and Albrecht D. Opposite effects secreted recombinant and plasma enzymes. J Biol Chem 266:
of angiotensin II and IV in the lateral nucleus of the amygdala. 5540 –5546, 1991.
Brain Res Bull 47: 311–315, 1998. 768. Weisinger RS, Blair-West JR, Burns P, Denton DA, and Tarjan
749. Von Bohlen und Hahlbach O and Albrecht D. Identification of E. Role of brain angiotensin in thirst and sodium appetite of rats.
angiotensin IV binding sites in the mouse brain by a fluorescent Peptides 18: 977–984, 1997.
binding study. Neuroendocrinology 72: 218 –223, 2000. 769. Welches WR, Brosnihan B, and Ferrario CM. A comparision of
750. Von Bohlen und Hahlbach O, Walther T, Bader M, and Al- the properties and enzymatic activity of three angiotensin process-
brecht D. Interaction between Mas and the angiotensin AT1 recep- ing enzymes: angiotensin converting enzyme, prolyl endopeptidase
tor in the amygdala. J Neurophysiol 83: 2012–2183, 2000. and neutral endopeptidase. Life Sci 52: 1461–1480, 1993.
751. Von Lutterotti N, Catanzaro DF, Sealey JE, and Laragh JH. 770. Weyhenmeyer JA, Raizada MK, Phillips MI, and Fellows RE.

Renin is not synthesized by cardiac and extrarenal vascular tissues. Presence of angiotensin II in neurons cultured from fetal rat brain.
A review of experimental evidence. Circulation 89: 493– 498, 1994. Neurosci Lett 16: 41– 46, 1980.
752. Wagner J, Danser AH, Derkx FH, de Jong TV, Paul M, Mullins 771. Whitebread S, Mele M, Kamber B, and de Gasparo M. Prelim-
JJ, Schalekamp MA, and Ganten D. Demonstration of renin inary biochemical characterization of two angiotensin II receptor
mRNA, angiotensinogen mRNA, angiotensin converting enzyme subtypes. Biochem Biophys Res Commun 163: 284 –291, 1989.
mRNA expression in the human eye: evidence for an intraocular 772. Whiting P, Nava S, Mozley L, Eastham H, and Poat J. Expres-
renin-angiotensin system. Br J Ophthamol 80: 159 –163, 1996. sion of angiotensin converting enzyme mRNA in rat brain. Mol
753. Wallace KB, Bailie MD, and Hook JB. Development of angio- Brain Res 11: 93–96, 1991.
tensin-converting enzyme in fetal rat lungs. Am J Physiol Regul 773. Widdop RE, Jones ES, Hannan RE, and Gaspari TA. Angioten-
Integr Comp Physiol 236: R57–R60, 1979. sin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol
140: 809 – 824, 2003.
754. Wallace KB, Bailie MD, and Hook JB. Angiotensin-converting
774. Williams TA, Villard E, Prigent Y, Dadoune JP, and Soubrier
enzyme in developing lung and kidney. Am J Physiol Regul Integr
F. A genetic study of angiotensin I-converting enzyme levels in
Comp Physiol 234: R141–R145, 1978.
human semen. Mol Cell Endocrinol 107: 215–219, 1995.
755. Wallace KB, Hook JB, and Bailie MD. Postnatal development of
775. Wilson CM, Cherry M, Taylor BA, and Wilson JD. Genetic and
the renin-angiotensin system in rats. Am J Physiol Regul Integr
endocrine control of renin activity in the submaxillary gland of the
Comp Physiol 238: R432–R437, 1980.
mouse. Biochem Genet 19: 509 –523, 1981.
756. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B,
776. Wilson SK, Lynch DR, and Snyder SH. Angiotensin-converting
Jupner A, Baur E, Nissen E, Vetter K, Neichel D, Duden- enzyme labeled with [3H]captopril. Tissue localizations and
hausen JW, Haller H, and Luft FC. Patients with preeclampsia changes in different models of hypertension in the rat. J Clin Invest
develop agonistic autoantibodies against the angiotensin AT1 re- 80: 841– 851, 1987.
ceptor. J Clin Invest 103: 945–952, 1999. 777. Winnicka MM. 6-OHDA bilateral lesions to the amygdala abolish
757. Walsh DA, Hu DE, Wharton J, Catravas JD, Blake DR, and the memory enhancing effect of angiotensin II in rats. Pharmacol
Fan TP. Sequential development of angiotensin receptors and Res 38: 53–58, 1998.
angiotensin I converting enzyme during angiogenesis in the rat 778. Winnicka MM, Braszko JJ, and Wisniewski K. Dopaminergic
subcutaneous sponge granuloma. Br J Pharmacol 120: 1302–1311, projection to the septum mediates facilitatory effect of angio-
1997. tensins on recognition memory in rats. Pharmacol Res 36: 387–394,
758. Walters PE, Gaspari TA, and Widdop RE. Angiotensin-(1O7) 1997.
acts as a vasodepressor agent via angiotensin II type 2 receptors in 779. Wintour EM, Moritz K, Butkus A, Baird R, Albiston A, and
conscious rats. Hypertension 45: 960 –966, 2005. Tenis N. Ontogeny and regulation of the AT1 and AT2 receptors in
759. Walther T, Balschun D, Voigt JP, Fink H, Zuschratter W, the ovine fetal adrenal gland. Mol Cell Endocrinol 157: 161–170,
Birchmeier C, Ganten D, and Bader M. Sustained long term 1999.
potentiation and anxiety in mice lacking the Mas protooncogene. 780. Wintroub BU, Klickstein LB, Dzau VJ, and Watt KW. Granulo-
J Biol Chem 273: 11867–11873, 1998. cyte-angiotensin system. Identification of angiotensinogen as the
760. Walther T, Voigt JP, Fukamizu A, Fink H, and Bader M. plasma protein substrate of leukocyte cathepsin G. Biochemistry
Learning and anxiety in angiotensin-deficient mice. Behav Brain 23: 227–232, 1984.
Res 100: 1– 4, 1999. 781. Wolny A, Clozel JP, Rein J, Mory P, Vogt P, Turino M, Kiowski
761. Wang D, Carretero OA, Yang XY, Rhaleb NE, Liu YH, Liao TD, W, and Fischli W. Functional and biochemical analysis of angio-
and Yang XP. N-acetyl-seryl-aspartyl-lysyl-proline stimulates an- tensin II-forming pathways in the human heart. Circ Res 80: 219 –
giogenesis in vitro and in vivo. Am J Physiol Heart Circ Physiol 227, 1997.
287: H2099 –H2105, 2004. 782. Wong PY, Fu WO, Huang SJ, and Law WK. Effect of angiotensins
762. Wang H, Delaney KH, Kwiecien JM, Smeda JS, and Lee RM. on electrogenic anion transport in monolayer cultures of rat epi-
Prevention of stroke with perindopril treatment in stroke-prone didymis. J Endocrinol 125: 449 – 456, 1990.
spontaneously hypertensive rats. Clin Invest Med 20: 327–338, 783. Wong PY and Uchendu CN. The role of angiotensin-converting
1997. enzyme in the rat epididymis. J Endocrinol 125: 457– 465, 1990.
763. Wang XP, Zhang R, Wu K, Wu L, and Dong Y. Angiotensin II 784. Wright JW, Dengerink HA, Miller JM, and Goodwin PC. Po-
mediates acinar cell apoptosis during the development of rat pan- tential role of angiotensin II in noise-induced increases in inner ear
creatic fibrosis by AT1R. Pancreas 29: 264 –270, 2004. blood flow. Hear Res 17: 41– 46, 1985.
764. Ward PE and Sheridan MA. Angiotensin I converting enzyme of 785. Wright JW and Harding JW. Important role for angiotensin III
rat intestinal and vascular surface membrane. Biochim Biophys and IV in the brain renin-angiotensin system. Brain Res 25: 96 –124,
Acta 716: 208 –216, 1982. 1997.

786. Wright JW, Stubley L, Pederson ES, Kramar EA, Hanesworth brain barrier functions revealed by renin-deficient mice. J Biol
JM, and Harding JW. Contributions of the brain angiotensin Chem 275: 5– 8, 2000.
IV-AT4 receptor subtype system to spatial learning. J Neurosci 19: 800. Yang F, Yang XP, Liu YH, Xu J, Cingolani O, Rhaleb NE, and
3952–3961, 1999. Carretero OA. Ac-SDKP reverses inflammation and fibrosis in rats
787. Wu JN, Edwards D, and Berecek KH. Changes in renal angio- with heart failure after myocardial infarction. Hypertension 43:
tensin II receptors in spontaneously hypertensive rats by early 229 –236, 2004.
treatment with the angiotensin-converting enzyme inhibitor capto- 801. Yang SN, Lippoldt A, Jansson A, Phillips MI, Ganten D, and
pril. Hypertension 23: 819 – 822, 1994. Fuxe K. Localization of angiotensin II AT1 receptor-like immuno-
788. Wyse B and Sernia C. Growth hormone regulates AT-1a angio- reactivity in catecholaminergic neurons of the rat medulla oblon-
tensin receptors in astrocytes. Endocrinology 138: 4176 – 4180, gata. Neuroscience 81: 503–515, 1997.
1997. 802. Yokoyama M, Hiwada K, Kokubu T, Takaha M, and Takeuchi
789. Xiao X, Chakraborti S, Dimitrov AS, Gramatikoff K, and M. Angiotensin-converting enzyme in human prostate. Clin Chim
Dimitrov DS. The SARS-CoV S glycoprotein: expression and func- Acta 100: 253–258, 1980.
tional characterization. Biochem Biophys Res Commun 312: 1159 – 803. Yoshimura R, Sato T, Kawada T, Shishido T, Inagaki M,
1164, 2003. Miyano H, Nakahara T, Miyashita H, Takaki H, Tatewaki T,
790. Xu Z and Johnson AK. Central renin injections: effects on drink- Yanagiya Y, Sugimachi M, and Sunagawa K. Increased brain
ing and expression of immediate early genes. Brain Res 782: 24 –35, angiotensin receptor in rats with chronic high-output heart failure.
1998. J Card Fail 6: 66 –72, 2000.
791. Xu Z and Xinghong J. Drinking and Fos-immunoreactivity in rat 804. Yoshimura Y, Karube M, Aoki H, Oda T, Koyama N, Nagai A,
brain induced by local injection of angiotensin I into the subforni- Akimoto Y, Hirano H, and Nakamura Y. Angiotensin II induces
cal organ. Brain Res 817: 67–74, 1999. ovulation and oocyte maturation in rabbit ovaries via the AT2
792. Yabuuchi F, Takahashi M, Aritake K, Fujimoto M, Ito H,

receptor subtype. Endocrinology 137: 1204 –1211, 1996.
Tsuzaki M, Akai T, Yamaguchi M, Hayashi S, Nishino Y, and
805. Yoshioka M, Erickson RH, and Kim YS. Digestion and assimila-
Brautigam M. Post-stroke treatment with imidapril reduces learn-
tion of proline-containing peptides by rat intestinal brush border
ing deficits with less formation of brain oedema in a stroke-prone
membrane carboxypeptidases. J Clin Invest 81: 1090 –1095, 1988.
substrain of spontaneously hypertensive rats. Fundam Clin Phar-
806. Yoshioka M, Erickson RH, Woodley JF, Gulli R, Guan D, and
macol 13: 475– 483, 1999.
Kim YS. Role of rat intestinal brush-border membrane angiotensin-
793. Yagami H, Kurauchi O, Murata Y, Okamoto T, Mizutani S, and
converting enzyme in dietary protein digestion. Am J Physiol Gas-
Tomoda Y. Expression of angiotensin-converting enzyme in hu-
man placenta and its physiologic role in the fetal circulation. Obstet trointest Liver Physiol 253: G781–G786, 1987.
Gynecol 84: 453– 457, 1994. 807. You D, Loufrani L, Baron C, Levy BI, Widdop RE, and Henrion
794. Yagil C, Sapojnikov M, Kreutz R, Zurcher H, Ganten D, and D. High blood pressure reduction reverses angiotensin II type 2
Yagil Y. Role of chromosome X in the Sabra rat model of salt- receptor-mediated vasoconstriction into vasodilation in spontane-
sensitive hypertension. Hypertension 33: 261–265, 1999. ously hypertensive rats. Circulation 111: 1006 –1011, 2005.
795. Yamada H, Akishita M, Ito M, Tamura K, Daviet L, Lehtonen 808. Zhao W, Leung PY, Chew SB, Chan HC, and Wong PY. Local-
JY, Dzau VJ, and Horiuchi M. AT2 receptor and vascular smooth ization and distribution of angiotensin II in the rat epididymis. J
muscle cell differentiation in vascular development. Hypertension Endocrinol 149: 217–222, 1996.
33: 1414 –1419, 1999. 809. Zheng J, Vagnoni KE, Bird IM, and Magness RR. Expression of
796. Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI, and basic fibroblast growth factor, endothelial mitogenic activity, and
Mendelsohn FAO. Localization of angiotensin converting enzyme angiotensin II type-1 receptors in the ovine placenta during the
in rat heart. Circ Res 68: 141–149, 1991. third trimester of pregnancy. Biol Reprod 56: 1189 –1197, 1997.
797. Yamada T, Horiuchi M, and Dzau VJ. Angiotensin II type 2 810. Zhu YZ, Chimon GN, Zhu YC, Lu Q, Li B, Hu HZ, Yap EH, Lee
receptor mediates programmed cell death. Proc Natl Acad Sci USA HS, and Wong PT. Expression of angiotensin II AT2 receptor in
93: 156 –160, 1996. the acute phase of stroke in rats. Neuroreport 11: 1191–1194, 2000.
798. Yan Y, Chen R, Pitarresi T, Sigmund CD, Gross KW, Sealey 811. Zhuo J, Moeller I, Jenkins T, Chai SY, Allen AM, Ohishi M,
JE, Laragh JH, and Catanzaro DF. Kidney is the only source of and Mendelsohn FA. Mapping tissue angiotensin-converting en-
human plasma renin in 45-kb human renin transgenic mice. Circ zyme and angiotensin AT1, AT2 and AT4 receptors. J Hypertens 16:
Res 83: 1279 –1288, 1998. 2027–2037, 1998.
799. Yanai K, Saito T, Kakinuma Y, Kon Y, Hirota K, Taniguchi- 812. Zurcher H, Van VP, Szpirer J, Szpirer C, and Kreutz R. Assign-
Yanai K, Nishijo N, Shigematsu Y, Horiguchi H, Kasuya Y, ment of the gene encoding renin binding protein (Renbp) to rat
Sugiyama F, Yagami K, Murakami K, and Fukamizu A. Renin- chromosome Xq37 by in situ hybridization and radiation hybrid
dependent cardiovascular functions and renin-independent blood- mapping. Cytogenet Genome Res 97: 277H, 2002.

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Physiol Rev 86:747-803, 2006. doi:10.1152/physrev.00036.2005

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