REVIEW

CURRENT
OPINION Monocyte chemoattractant protein-1 and
the kidney
Hermann Haller, Anna Bertram, Felix Nadrowitz, and Jan Menne

Purpose of review
Recently, initial studies have been carried out in patients using monocyte chemoattractant protein-1 (MCP-1)
inhibitors. This review summarizes the known function of MCP-1 in regulating monocytes during
inflammation and its role in inflammatory disease of the kidney.
Recent findings
MCP-1 is one of the first chemokines described and plays an important role in renal inflammatory disease.
The function of MCP-1 has been investigated and analyzed in both animal models of renal disease and
renal patients. MCP-1 mediates firstly the release of monocytes from the bone marrow, and then generates
a gradient in the endothelial glycocalyx to direct monocytes to sites of inflammation, thereby alleviating the
migration of blood leukocytes into the inflamed tissue. In addition, MCP-1 has direct signaling effects in
monocytes and influences migration, proliferation, and differentiation of leukocytes. Blockade of MCP-1 in
several models of renal disease has ameliorated the disease, suggesting that inhibition of MCP-1 is a
promising and valid strategy to treat patients with renal inflammatory disease.
Summary
Understanding the role of MCP-1 in monocyte homeostasis and the implications of MCP-1 inhibition in
renal disease will help in designing better diagnostic and therapeutic strategies in patients with
inflammatory renal disease.
Keywords
bone marrow, diabetes, endothelium, glycocalyx, inflammation, kidney disease, monocyte
chemoattractant protein–1

INTRODUCTION tissue injury. Chemokines such as MCP-1 are

Monocyte chemoattractant protein-1 [MCP-1/che-
mokine (C-C motif) ligand 2] is a member of the
chemokine family. Chemokines (chemotactic cyto-
kines) are small (5–20 kDa) heparin-binding
proteins that constitute a large family of similar
peptides with a high homology between its mem-
bers. At present, there are more than 50 human
chemokines and 20 G-protein-coupled chemokine
receptors described. MCP-1 was one of the first
chemokines identified, and has been extensively
studied over the last 30 years (for reviews see
[1,2]). Chemokines can be structurally classified into
four subfamilies named C-X-C, C-C, C-X3-C, and C
on the basis of the number and location of the
cysteine residues C at the N-terminus of the mol-
ecule [3]. Chemokines can also be grouped into two
main functional families, namely inflammatory and
homeostatic. The main function of MCP-1 is to
regulate inflammatory cell trafficking and control
the recruitment of leukocytes in inflammation and
secreted in response to signals such as proinflam-
matory cytokines and they play an important role in
selectively recruiting monocytes, neutrophils, and
lymphocytes. MCP-1 is a potent chemotactic factor
for monocytes [4] and it plays an important role in
various pathophysiological conditions in many
organ systems [5,6]. Once induced, the chemokines
form a chemical ligand gradient or chemokine gra-
dient for the directed migration of cells expressing
the appropriate chemokine receptors [7]. This gra-
dient is formed along extracellular structures such as
Department of Nephrology and Hypertension, Medizinische Hochschule
Hannover, Hannover, Germany
Correspondence to Professor Hermann Haller, Department of Nephrol-
ogy and Hypertension, Medizinische Hochschule Hannover, Carl-Neu-
berg-Str.1, 30559 Hannover, Germany. Tel: +0049 511 5326319; fax:
+0049 511 552366; e-mail: haller.hermann@mh-hannover.de
Curr Opin Nephrol Hypertens 2016, 25:42–49
DOI:10.1097/MNH.0000000000000186

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 Monocyte chemoattractant protein-1 and the kidney Haller et al.
KEY POINTS
 MCP-1 is the most important chemokine for the
regulation of monocytes in inflammatory diseases.
 MCP-1 influences the release of monocytes from the
bone marrow and generates a chemokine gradient to
guide monocytes into inflamed tissue.
 Inhibition of MCP-1 has been shown to ameliorate a
variety of inflammatory renal diseases, including
diabetic nephropathy.
 The initial studies in patients with diabetic nephropathy
are promising and support MCP-1 inhibition as a
therapeutic strategy in renal diseases.
the heparan sulfate glycosaminoglycans of the gly-
&
cocalyx [8 ]. The chemokine gradient allows cells
expressing the corresponding surface receptors to
move toward high local concentrations of chemo-
kines. Interestingly, several chemokines only func-
tion after their interaction with glycosamino-
&&
glycans [9 ].
Structure–function studies have shown that the
N-terminal region of MCP-1 is important for recep-
tor binding and activation [10]. MCP-1 acts by bind-
ing to the G-protein-coupled 7-transmembrane
domain CC chemokine receptor 2 (CCR2) on mono-
cytes. MCP-1 binding leads to intracellular calcium
release by stimulation of the phospholipase C-IP3
pathway and activation of protein kinase C (PKC)
[11]. PKC activates nuclear factor-kappaB, which
upregulates several genes that produce directional
cell motion. MCP-1–CCR2 binding also activates
Rho family proteins, which influence cell motility
through regulation of actin-dependent processes.
Other intracellular kinases, such as ERK1, ERK2,
JAK2, JNK1, and p38 are also known to be involved
in MCP-1 signal transduction [12,13]. It is important
to note that chemokines have chemotactic potential
for diverse receptors, even on the same cell type.
MCP-1 is expressed in a large variety of cell
types. Large amounts of MCP-1 are found in endo-
thelial cells, fibroblasts, and mononuclear cells. In
the kidney, cell types producing MCP-1 are tubular
cells, smooth muscle cells, mesangial cells, podo-
cytes, and also infiltrating cells such as eosinophils
and mast cells. The expression of MCP-1 at the
transcriptional level is also influenced by a variety
of stimuli. The main inducers of MCP-1 expression
are IL-1, tumor necrosis factor alpha, and interferon
gamma, but other cytokines or growth factors,
such as IL-4, M-CSF (colony stimulating factors),
GM-CSF, platelet-derived growth factor, trans-
forming growth factor–beta (TGF-b), as well as
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lipopolysaccharides, reactive oxygen species, and
immune complexes can induce MCP-1 [6,12–14].
Suppressors of MCP-1 are anti-inflammatory mol-
ecules, especially retinoic acid and glucocorticoids.
Unlike the almost ubiquitous expression of
MCP-1, its receptor CCR-2 is much more restricted
to a few cell types. As two splice variants of the CCR-
2 exist, CCR2A is the isoform expressed by mono-
nuclear cells and vascular smooth muscle cells,
whereas monocytes and activated natural killer cells
express predominantly the CCR2B isoform [15]. It is
important to note that apart from its inflammatory
cellular effects, CCR2 plays an anti-inflammatory
role in regulatory T cells.
Monocyte chemoattractant protein-1:
mechanisms and pathways of monocyte
recruitment
Before describing the role of MCP-1/CCR-2, it is
important to discuss the pathways and recruitment
of monocytes under physiological and pathophy-
siological conditions to understand the pathophy-
siological role of monocytes in renal disease and the
&& &
implications of therapeutic strategies [16 ,17 ].
Monocytes are a group of cells circulating in the
blood, bone marrow, and spleen, and constitute
10% of the total leukocytes. Monocytes can
remain in the circulation for up to 1–2 days after
which time, if they have not been recruited into
inflamed tissue, they die and are removed. Mono-
cytes originate in the bone marrow from hemato-
poietic stem cells (HSCs) and develop through a
series of sequential differentiation stages. Under
homeostatic conditions, monocytes are moved from
the bone marrow and circulate via the blood into the
tissue. Blood monocytes enter tissues and become
either macrophages, for example, in the gut, lung,
and dermis (monocyte-derived macrophages or
monocyte-derived tissue-resident macrophages). It
is important to understand that some tissue macro-
phages, the so-called tissue-resident macrophages
derived directly from yolk sac during the embryo-
genesis (for instance microglia, liver Kupffer cells,
and tubulo-interstitial macrophages in the kidney),
are long lived, remain in their respective tissue, and
are mainly maintained by self-renewal. To make
things even more complicated, blood-derived
monocytes may act as resident macrophages of
the vasculature, contributing to homeostasis by
patrolling and monitoring the endothelial surface
in the blood vessel lumen. During an inflammatory
reaction, the number of blood monocytes recruited
to the blood stream and into an inflamed tissue
increases considerably. A large majority of these cells
give rise to the inflammatory monocyte-derived
www.co-nephrolhypertens.com 43
Hormones, autacoids, neurotransmitters and growth factors

M-CSF

Common myeloid progenitor Monocytes/precursors

CCR2 dependent
Bone marrow

CCR2

Inflamed monocytes

Blood

CD11b+
Kidney
LyBC*
F4/80low

Macrophages

Release of soluble factors

(TNFα, IFNγ, NO, ROS, PDGF,TGF-β)

Proteinuria Tubulointerstitial fibrosis Glomerulosclerosis

ESRD

FIGURE 1. Functions of MCP-1 in renal disease. Firstly, MCP-1 recruits monocytes and precursors from the bone marrow into the
blood stream. This first recruitment step seems to be increased under inflammatory conditions and is most likely mediated by
circulating MCP-1. Secondly, MCP-1 is released at sites of inflammation and stored in the local glycocalyx, thereby forming a
chemokine gradient, and recruits circulating monocytes into the inflamed tissue. Thirdly, the locally produced MCP-1 induces
differentiation and inflammatory cytokines in the tissue monocytes/macrophages. On all three levels, MCP-1 is therefore active
and orchestrates the inflammatory response through mobilization, localization, recruitment, and differentiation. CSF, colony
stimulating factors; ESRD, end stage renal disease; IFN, interferon; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide;
ROS, reactive oxygen species; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.

macrophages, whereas some of them, which do not
differentiate into macrophages and remain as mono-
cyte-like cells, are able to take up antigens and
migrate to the draining lymph nodes, the so-called
tissue monocytes. In addition to the influx of
monocytes from the blood during inflammation,
all resident mononuclear cells in the tissue (tissue-
resident macrophages, monocyte-derived tissue
macrophages, and inflammatory monocyte-derived
macrophages) are activated and differentiate into
inflammatory cells following interaction with patho-
genic and damaged signals/insults in the interstitial
&&
microenvironment [18 ].
MCP-1 has three distinct roles in this scenario
(Fig. 1). Firstly, MCP-1 recruits monocytes and pre-
cursors from the bone marrow into the blood
stream. This first recruitment step seems to be
increased under inflammatory conditions and is
most likely mediated by circulating MCP-1. Sec-
ondly, MCP-1 is released at sites of inflammation
and stored in the local glycocalyx, thereby forming
a chemokine gradient, and it recruits circulating
monocytes into the inflamed tissue. Thirdly, the
locally produced MCP-1 induces differentiation
and inflammatory cytokines in the tissue mono-
cytes/macrophages. On all three levels, MCP-1
is therefore active and orchestrates the inflamma-
tory response through mobilization, localization,
recruitment, and differentiation.
Lastly, it has to be mentioned that there is an
increasing amount of evidence suggesting that
MCP-1 plays a role beyond that of a chemoattrac-
tant protein and influences other cell types in the
kidney directly. Mesangial cell exposure to MCP-1

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 Monocyte chemoattractant protein-1 and the kidney Haller et al.
induced an increase in inflammatory molecules,
that is, intercellular expression of adhesion mol-
ecule-1 (ICAM-1) as well as interstitial matrix mol-
ecules such as fibronectin [19,20]. In human tubular
epithelial cells, MCP-1 stimulates IL-6 secretion and
ICAM-1 synthesis [21]. Furthermore, in podocytes,
MCP-1 binding to the CCR2 receptor induces
migration of podocytes and a significant reduction
of both mRNA and protein expressions of nephrin
[22,23]. This scenario is the background for our
understanding of MCP-1 and macrophages in
renal disease.
Monocyte chemoattractant protein-1 and
renal disease
MCP-1 was first detected and described in membra-
nous nephropathy, IgA nephropathy, and glomer-
ulosclerosis. MCP-1 staining in tubular epithelial
cells was stronger and correlated with interstitial
infiltration of macrophages [24]. Since then, detec-
tion of MCP-1 in renal tissues as well as in urine
samples has been studied in various renal diseases.
In systemic lupus erythematodes (SLE), the
important role of MCP-1 has been shown in animal
models and patients with the disease. In animal
models of lupus nephritis, the expression of MCP-
1 in glomeruli and tubular epithelial cells is mark-
edly increased together with the infiltration of
macrophages and progression of nephritis (glomer-
ular hypercellularity, glomerulosclerosis, crescent
formation, and vasculitis). Several therapeutic strat-
egies to inhibit MCP-1 activity or expression of
MCP-1 have shown that both signs of inflammation
and progression of the disease are markedly reduced
[25–30]. Importantly, the subcutaneous injection
of nuclease-resistant RNA oligonucleotides (Spie-
gelmer) and the infiltration of macrophages and
T cells were all markedly reduced in MRL/lpr mice
[30]. These data demonstrate the importance of
MCP-1 and MCP-1/CCR2-associated therapeutic
strategies in lupus nephritis.
In contrast, for patients with lupus nephritis, so
far there is only indirect evidence that MCP-1 plays
an important role in the disease. Expression of
MCP-1 was detected in renal tissues from patients
with active lupus nephritis (WHO classes III and IV).
Expression of MCP-1 was mainly found in the
tubules, peritubular capillary endothelial cells,
and infiltrating mononuclear cells [30]. Several stud-
ies investigating urinary MCP-1 as a potential bio-
marker have also been performed in patients with
lupus nephritis. The levels of urinary MCP-1 were
significantly higher in patients with active lupus
nephritis than in patients with inactive disease or
in healthy controls [31–36]. Elevated levels of
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urinary MCP-1 decreased significantly after steroid
therapy. These results support the hypothesis that
MCP-1 is involved in the pathogenesis of lupus
nephritis, especially via the recruitment and acti-
vation of macrophages in the renal interstitium. In
addition, the measurement of urinary MCP-1 level
may be a useful clinical tool for monitoring the
disease activity in patients with lupus nephritis
[31]. It is interesting that the increase of urinary
MCP-1 preceded a relapse by 2–4 months. In
addition, patients who responded to therapy
showed a slow decline in urinary MCP-1, whereas
nonresponders had persistently high urinary MCP-
1. These findings suggest that urinary MCP-1 is a
sensitive and specific biomarker of renal SLE and its
severity. There are also studies investigating the
association of MCP-1 gene polymorphism and the
risk of renal disease in lupus patients. SLE patients
with an A/G or G/G MCP-1–2518 genotype had
increased MCP-1 production both peripherally
and within the kidney and showed a higher risk
of developing lupus nephritis [37,38].
Vasculitis and crescent formation
To study MCP-1 expression in acute glomerulo-
nephritis, the model of nephrotoxic GBM-induced
nephritis model has mostly been used [39,40]. After
treatment with a neutralizing antibody to MCP-1,
there was a reduction in the number of glomerular
macrophages, a reduction in proteinuria, and a
decrease in crescent formation and less interstitial
fibrosis in this rat model [40–42]. However, the
location of MCP-1 expression was found predom-
inantly in tubular cells and not glomeruli. It has
therefore been suggested that MCP-1 promotes
tubulointerstitial injury, but is not implicated in
glomerular damage [43]. However, in other renal
diseases, such a phenomenon has not been
observed, raising the possibility that monocyte
influx or MCP-1 expression is differentially influ-
enced in different renal diseases [44].
Detection of MCP-1 has been shown in
several studies of patients with acute glomeruloneph-
ritis. Also, in the human studies, discrepancies
regarding the location of MCP-1 have been demon-
strated. In most studies, MCP-1 was detected in infil-
trating macrophages in both glomeruli and the
tubulointerstitial lesions [45–47]; however, in
another study, MCP-1 was mainly detected in
the interstitium and not in glomeruli [48]. These
studies demonstrate that MCP-1 is expressed in
both infiltrating and resident renal cells in acute
glomerulonephritis.
In accordance with the increased expression of
MCP-1 in renal tissue, urinary MCP-1 was increased
www.co-nephrolhypertens.com 45
Hormones, autacoids, neurotransmitters and growth factors
in patients with acute glomerulonephritis, even
in comparison with urinary levels of MCP-1 in
other renal diseases [48,49]. Urinary MCP-1 levels
correlated significantly with infiltrating monocytes
with anti-neutrophil cytoplasmic antibodies titre
and with proteinuria. After initiation of therapy,
urinary MCP-1 level decreases significantly.
Over the last 30 years, MCP-1 expression in renal
biopsies and the excretion of MCP-1 in the urine has
found to be increased in most states of inflammatory
kidney disease. Several studies in patients with IgA
nephropathy have shown an association between
MCP-1 and the severity of the renal lesions
suggesting the use of MCP-1 as a biomarker in this
disease [50–53]. Another interesting example of the
possible importance of MCP-1 as a biomarker is
allograft rejection in kidney transplantation. In
patients with acute rejection in the transplant, the
MCP-1 expression was significantly higher than in
mere tubular damage. The localization of MCP-1
was found mostly in the proximal tubular cells of
the transplanted kidney and in the infiltrating
mononuclear cells [54,55]. Urinary MCP-1 excretion
was also significantly higher in patients with acute
rejection than in patients with stable graft function.
As seen in other inflammatory diseases, a significant
reduction of urinary MCP-1 was observed in patients
who responded to steroid treatment.
Monocyte chemoattractant protein-1 in
diabetic nephropathy
We have recently carried out the first study using a
MCP-1 inhibitor in patients with renal disease. We
chose a group of patients with established diabetic
nephropathy to test the hypothesis that monocytes/
macrophages and MCP-1 play an important role in
diabetes-induced renal damage. To inhibit MCP-1,
we used the Spiegelmer emapticap pegol (NOX-
E36), a 40-nucleotide PEGylated L-RNA oligonucleo-
tide that specifically binds and inhibits MCP-1 with
high affinity and specificity.
Diabetic nephropathy has been traditionally
viewed as a disease of increased fibrosis and hyali-
nosis and not so much of an inflammatory condition.
It has been, as in most forms of chronic kidney
disease, characterized by progressive fibrosis that
eventually affects all substructures of the kidney with
the final consequence of end-stage renal disease.
Accelerated matrix deposition has been described
even in early stages of diabetic renal disease with or
without microalbuminuria [56]. In diabetic kidneys,
glomerular deposition of collagen IV, V, laminin, and
fibronectin is increased in early and moderately
advanced stages in the mesangial matrix and glomer-
ular basement membranes [57], whereas type I and III
46 www.co-nephrolhypertens.com
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collagen appear in the late stages of glomeruloscle-
rosis [58,59]. The source of the increased fibrotic
molecules are a heterogeneous group of interstitial
cells derived from a variety of cellular origins such as
resident mesenchymal cells, tubular epithelial cells,
circulating fibrocytes, and bone marrow-derived
stem cells, and macrophages which populate the
renal tubulointerstitial space during early fibrogene-
sis and communicate with each other, and surviving
parenchymal cells, via a complicated network of
cytokines and adhesion molecules. These cells secrete
abundant extracellular matrix to achieve architec-
tural remodeling in parallel with functional
deterioration. Renal fibrosis is a dominant determi-
nant of the clinical outcome of patients and has been
(and still is) an attractive therapeutic target to ameli-
orate or prevent diabetic nephropathy. However, for
the most part, current ‘antifibrotic’ therapies are
ineffective or have only marginal effects.
The cause for the increased fibrosis in diabetic
renal disease has for a long time associated with the
metabolic disturbances in diabetes, that is, direct
effects of glucose and advanced glycosylation end
product (AGE)-derivatives on renal cells. In this
concept, high extracellular glucose induces a num-
ber of signaling pathways that lead to enhanced
extracellular material (ECM) production directly
via PKC stimulation [60,61] of AP-1 transcriptional
activation, ERK pathways, and TGF-b1 synthesis
[62], which, in an autocrine and paracrine fashion,
stimulates its signaling pathways to stimulate ECM
protein synthesis. Indeed, high glucose and AGEs
can induce both fibrosis-inducing factors such as
TGF-b and connective tissue growth factor [63,64].
Inflammation has not been considered to be a
major pathophysiological player in diabetic nephr-
opathy until recently. This is in contrast to the
important role of inflammation in most other renal
diseases where inflammation has always been
regarded as the major trigger for the induction of
fibrosis [65]. However, recent studies have shown
that kidney inflammation is crucial in promoting
the development and progression of diabetic nephr-
opathy. Inflammation maybe a key factor which is
activated by the metabolic, biochemical, and hemo-
dynamic derangements known to exist in the dia-
betic kidney [66]. As early as 1991, Bohle et al. [67]
observed that the inflammation of the renal inter-
stitium seen in diabetes contains monocytes, macro-
phages, T lymphocytes, fibroblasts, and fibrocytes.
These findings were supported by Furuta et al. [68]
who found that the number of macrophages
increased significantly in the moderate stage of glo-
merulosclerosis. Evidence from several renal biopsy
studies has shown that macrophage accumulation in
diabetic kidneys predicts declining renal function
Volume 25  Number 1  January 2016
 Monocyte chemoattractant protein-1 and the kidney Haller et al.
[69,70]. Correlations between the degree of macro-
phage infiltration and severity of renal injury in
humans, and in temporal studies in rodents, suggest
an effector function for macrophages. STZ-induced
diabetic animal models indicate that macrophage
accumulation is associated with kidney fibrosis
[71]. It is believed that macrophages play a crucial
role in renal fibrogenesis [69,70].
Our clinical study was based on several exper-
imental studies demonstrating that MCP-1 plays an
important role in diabetic nephropathy. In STZ-
induced hyperglycemia and db/db mice, MCP-1
deletion reduced glomerular and interstitial infiltra-
tion of macrophages and histological damage
[71–73]. These findings were confirmed in a sub-
sequent animal study in which MCP-1 blockade
with a Spiegelmer reduced glomerular macrophages
by 40%, improved diffuse glomerulosclerosis, and
inhibited the progressive decline of glomerular
filtration rate in uninephrectomized db/db mice
[74]. Recent studies have also demonstrated that
blocking the MCP-1 receptor CCR2 with three differ-
ent compounds improves diabetic kidney injury
and glycemic control in a type 2 db/db mice model
[75–77]. These data have led to speculation that
blockade of the MCP-1/CCR2 axis might be a mean-
ingful new therapeutic target to treat patients with
diabetic kidney injury [78,79].
Indirect evidence for our hypothesis comes also
from other studies. In a study examining the effect of
intensive insulin therapy on urinary MCP-1 and
ICAM-1, the urinary levels of both decreased signifi-
cantly after 2 weeks of intensive insulin therapy [80].
Tam et al. [81] have evaluated the prognostic value
of urinary MCP-1 and found that urinary levels of
MCP-1 were higher in patients with macroalbumi-
nuria than in patients with normo or microalbumi-
nuria. Over a follow-up of 6 years, urinary MCP-1
correlated significantly with the rate of deterioration
of renal function [81]. These findings have been
recently confirmed and extended in a prospective
&
analysis by Fufaa and colleagues [82 ]. Therefore,
based on the relationship between MCP-1 expression
and monocyte infiltration on the one hand, and the
promising results of the animal experiments on the
other we treated 76 patients in a randomized, double
blind, placebo-controlled multicenter phase II, a
proof of concept study. The results of the study have
&
been published in abstract form [83 ,84]. The primary
objective was to characterize the effect of MCP-1
inhibition on the change in urinary albumin creati-
nine ratio. The Spiegelmer was administered subcu-
taneously twice weekly for 85 days, followed by a
treatment-free observation period of 12 weeks. We
observed two effects of MCP-1 inhibition in this study
which are especially intriguing: it takes more than
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2 months of treatment until the beneficial effects
versus placebo become evident; the effects are main-
tained after cessation of treatment for a prolonged
period of time. Such a profile is clearly different from
other agents known to decrease albuminuria (e.g.
renin–angiotensin system blockers or endothelin
receptor antagonists) which are characterized by a
swift onset of effect as well as a rapid return to baseline
after stop of dosing [85–88]. Most likely, the temporal
course of the antiproteinuric effect of MCP-1 inhi-
bition reflects the anti-inflammatory mechanism of
this strategy. We assume, although biopsies are not
available in these patients, that it takes several days of
MCP-1 inhibition to interfere with the release and
uptake of monocytes from the bone marrow and into
renal (and other) tissues. Such an assumption would
be in accordance with the time course of monocyte/
macrophage turnover described above. In a couple of
patients, we assessed circulating monocytes and
observed a rapid decline within 24 h. This finding
would suggest that the MCP-1 blockade has a rapid
effect on the MCP-1-mediated release of monocytes
from the bone marrow and reduces the pool of cir-
culating possible inflammatory monocytes. The
reduction of infiltrated monocytes in the kidney
would take much longer, that is, several weeks. Only
after clearance of inflammatory monocytes from the
renal tissue could a beneficial effect on proteinuria
could be observed. However, such a hypothesis
explains the long-lasting effect of MCP-1 inhibition
on proteinuria. Even after several weeks, we did not
observe an increase in proteinuria in our diabetic
patients. It will be interesting to see how long the
antiproteinuric effect will last and whether intermit-
tent treatment strategies in the blockade of MCP-1 are
feasible. We also observed a reduction of HbA1c in
our patients. Interestingly, the time course of this
effect was similar to the antiproteinuric effect. Our
interpretation would be a reduction of monocytes
and inflammation in other nonrenal tissues, which
contribute to insulin resistance such as fat cells or
vascular cells. However, at present, we cannot rule
out other effects of MCP-1 blockade, that is, an effect
on monocyte differentiation [88,89].
An important issue is the question of whether
inhibition of MCP-1 leads to an increase in infection
and reduced immunological response in patients.
However, after having treated more than 100 patients
with MCP-1 inhibition over several months, no
increased susceptibility for infection was observed.
CONCLUSION
To summarize, MCP-1 seems to be a key player in
the pathogenesis of inflammatory renal disease.
In addition, it also seems to orchestrate an
www.co-nephrolhypertens.com 47
Hormones, autacoids, neurotransmitters and growth factors
inflammatory response in renal disease where
inflammation so far has not played a major role,
such as in diabetic nephropathy. MCP-1 influences
the whole cascade of the monocyte-associated
inflammation from (1) release of monocytes from
the bone marrow, (2) building a chemokine gradient
for adhesion and infiltration, (3) being involved in
stimulation, and possible differentiation of mono-
cytes and macrophages in the kidney [88,89]. The
ablation studies in animals have shown that MCP-1
is a safe target, and the first preliminary findings in
patients support that conclusion. Despite current
treatment strategies, the residual risk for disease
progression in patients with diabetic nephropathy
is still high. MCP-1 inhibition and reduction of
monocyte/macrophage infiltration seem to be
promising targets for future treatment of diabetic
nephropathy [90].
Acknowledgements
The authors would like to thank S. Altenhofen and A.
Kreipe for assistance with the study.
Financial support and sponsorship
This work was supported by the Department of Neph-
rology, Hannover Medical School, Hannover, Germany
Conflicts of interest
H.H. has received honoraria from Bayer Inc, Astra-
Zeneca, Janssen, Novo-Nordisk, Noxxon, and Alexion.
The remaining authors have no conflicts of interest.
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