Beruflich Dokumente
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A R T I C L E
I N F O
Article history:
Received 11 February 2012
Accepted 1 March 2012
Keywords:
Diabetic nephropathy
Glomerulosclerosis
Pathophysiology
Tubulointerstitial fibrosis
A B S T R A C T
Diabetes is the major cause of chronic kidney disease which in turn may lead to end-stage renal disease
(ESRD) ending up in dialysis. Hemodynamic and structural changes following diabetes are working together
in the process of development of diabetic nephropathy (DN). Hyperglycemia-induced metabolic and hemodynamic pathways are proven to be the mediators of kidney disease. Hyperglycemia causes the formation of
Amadori products, which are the altered proteins and advanced glycation end products (AGE) are the molecular players in the phases of DN. According to recent studies, activation of electron transport chain induced
by hyperglycemia can result in an increase in the reactive oxygen species (ROS) formation, which is thought
to be the initiating event in the development of complications in diabetes. Hemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, and interstitial inflammation are the steps in the advancement of DN. High glucose, AGEs,
and ROS act in unison to induce growth factors and cytokines through signal transduction pathways involving
protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-B. Transforming growth
factor (TGF)- causes hypertrophy of the renal cells and accumulation of extracellular matrix. Activation of
rennin angiotensin system with the subsequent formation of angiotensin-II (ANG-II) is involved in almost
all the steps in the development of DN. Blocking the action of ANG-II has a crucial role in every therapeutic
regimen to prevent and treat DN.
Copyright 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.
Introduction
The common cause for end-stage renal disease (ESRD) in developing
countries is diabetic nephropathy (DN) and studies suggest that
there are chances of increase in this number in future.1,2 In contrast
to the previous belief that type 2 diabetes mellitus (DM) is a benign
condition related to normal ageing process, this is projected as the
main single cause of renal failure in the USA, Japan, and Europe.35
The present data showing 10 million people with diabetes will double by 2030 in the US.6 The financial requirements for maintenance
of dialysis in patients with ESRD due to type 2 DM are higher compared to non-diabetic ESRD patients. The mortality of these patients
is higher owing to the cardiovascular complications.4,5 The thorough
knowledge of the pathophysiology of this disease is very essential
in order to develop newer therapeutic concepts for the prevention of
DN.7 The renal injury in DN is due to a complex series of pathophysiological changes initiated by disturbed glucose homeostasis.
The basic pathophysiology of DN is similar in both type 1 and type 2
DM patients.2 Moreover, co-morbidities like hypertension, obesity,
dyslipidemia, and arterial sclerosis impart more injury to the kidney
forming complex patterns of nephropathy. Even though there are
strong genetic determinants in the risk of nephropathy, only 4050%
of patients with type 1 or type 2 DM will eventually end up in nephropathy.8 The strategies to determine the genetic loci for DN susceptibility are genomic screening and polymorphism of candidate gene
*Corresponding author.
E-mail address: chinthavinod@sify.com
ISSN: 2211-9477 Copyright 2012. Reed Elsevier India Pvt. Ltd. All rights reserved.
doi: 10.1016/S2211-9477(12)70005-5
Hemodynamic pathways
Glomerular hemodynamic changes occurs very early in DN, which
include hyperfiltration and hyperperfusion injuries.14 There is a decrease in both afferent and efferent arteriolar resistance which is more
on the afferent side leading to increased glomerular capillary pressure
that enhances trans-capillary hydraulic pressure gradient as well as
122
Metabolic pathway
Hyperglycemia
AGE
PKC pathway
Polyol pathway
Oxidative stress
Hemodynamic pathways
High pressure
RAAS
VEGF
TGF-
Endothelin
Table 1
Renal structural abnormalities found in diabetic nephropathy.
Mesangial expansion
Glomerulosclerosis (diffuse, nodular)
Fibrin cap lesion
Capsular drop lesion
Basement membrane thickening (glomerular and tubular)
Endothelial foam cells podocyte abnormalities
Armanni-Ebstein cells (proximal tubules stuffed with glycogen)
Tubular atrophy
Interstitial inflammation
Interstitial fibrosis
Arteriosclerosis
an increase in glomerular plasma flow.14 Hyperperfusion and hyperfiltration are also said to be due to factors such as prostanoids, nitric
oxide, atrial natriuretic factor, growth hormone, glucagon, insulin and
angiotensin-II (ANG-II).14 The changes leading to glomerulosclerosis
are elevated intraglomerular pressure, increase in mesangial cell matrix
production and thickening of glomerular basement membrane.15,16
Hyperglycemia stimulate the synthesis of ANG-II, which exert hemodynamic, trophic, inflammatory and profibrinogenic effects on renal
cells.15,17 The factors that mediate hyperfiltration injury include
vascular endothelial growth factors (VEGF) and cytokines such as
transforming growth factor-beta (TGF-).15 The key role in diabetic
vascular derangement can be attributed to TGF-. the mechanism
is the increase NO production by the up-regulation of endothelial
NO synthase (eNOS) mRNA expression and by enhancing arginine
resynthesis.18,19
Alteration of glomerular hemodynamics due to shear stress and
mechanical strain, induce the autocrine and/or paracrine release of
cytokines and growth factors.16 Hemodynamic stress causes structural
changes of DN by the local activation of cytokines and growth factors. Increase in reabsorption of sodium chloride in proximal tubules
or loops of Henle leads to an increase in the glomerular filtration rate
by an intact macula-densa mechanism and hypertrophy of tubules
that mediate stimulated sodium chloride reabsorption could be pivotal in this process, linking again structural changes with hemodynamic adaptation in DN.20
Pathological changes
The hallmark of DN is nodular glomerulosclerosis and described by
Kimmelstiel and Wilson. Diabetes mellitus causes injury of all renal
compartments (Table 1) such as glomerulosclerosis, vascular diseases
and changes of the tubulointerstitium with tubular atrophy and interstitial fibrosis.2125
Increase in extracellular matrix and mesangial cell hypertrophy
causes expansion of the mesangial area which is the earliest morphological change of DN.23 Mesangial cell proliferation comes to us a
standstill in the G1-phase of the cell cycle by P 27Kip1 due to the effect of hyperglycemia. The ANG-II also enhances P 27Kip 1 which is the
mediator of G1-phase arrest. Blockade of ANG-II increases glucose
mediated mesangial injury.2631
Glomerular basement membrane (GBM) thickening starts as early
as 1 year after onset of type 1 diabetes31 which progresses over the
Metabolic pathways
The glucose transport activity is an important modulator of extracellular formation of mesangial cells. Glucose transporter-1 (GLUT-1)
is a key regulator of glucose entry in to kidney cells and the glucose
activates various metabolic pathways leading to mesangial expansion
and mesangial cell matrix production, mesangial cell apoptosis and
structural changes.40 If there is overexpression of GLUT-1, similar
changes will be induced in a renal cell even if the glucose levels is
normal.41,45 Mesangial cells express insulin-sensitive extracellular glucose transporters (GLUT-4) as well as a brain type of glucose transporters (GLUT-1) through which excessive glucose could easily enter
the cell in an insulin-independent manner.43,44
Non-enzymatic glycosylation that produce advanced glycosylation
end products (AGE), activation of protein kinase C (PKC), and acceleration of the polyol pathway along with hemodynamic changes results in the activation of VEGF, TGF-, interleukin-1 (IL-1), IL-6 and
IL-18 and tumor necrosis factor alpha (TNF-). All these pathways
act in unison leading to increased albumin permeability in GBM and
extracellular matrix accumulation, resulting in increasing proteinuria, glomerulosclerosis and finally tubulointerstitial fibrosis.
Oxidative stress
Increase in oxidative stress and the overproduction of reactive oxygen species (ROS) in diabetes is occurring due to hyperglycemia. This
ROS induces peroxidation of cell membrane lipids, oxidation of proteins, renal vasoconstriction and deoxyribonucleic acid (DNA) damage. Various biochemical pathways are also stimulated through the
increased generation of ROS mainly PKC pathways, AGE formation,
TGF-, and ANG-II.
Hyperglycemia
Mitochondrial ROS
Oxidative stress
Protein kinase C
Sorbitol
Prostanoids
Cytokines
AGEs
NF + B
Figure 2 Reactive oxygen species as a common mediator of pathophysiological effects of hyperglycemia. Increased uptake of glucose into cells leads to stimulated mitochondrial reactive oxygen species formation. This oxidative stress, in turn, activates
different processes involving protein kinase C, NF-B, cytokines, formation of advanced glycation end products, and others. AGE: advanced glycation end products,
NF: nuclear factor, ROS: reactive oxygen species.
Polyol pathways
Conversion of glucose to sorbitol by aldose reductase and then to
fructose by sorbitol dehydrogenase is occurring in the polyol pathway.
An increased glucose uptake into the cell causes entry of more glucose
into the polyol pathway. Reduction of glucose to sorbitol requires
NADPH-depleting cells of an important substrate for the regeneration
of glutathione which exacerebrates intracellular oxidative stress. Threedeoxyglucone which is intermediate, is a precursor of AGEs.4347
123
124
High glucose
ROS
ANG-II
Proteinuria
Nuclear factor-kB
Nuclear factor-B plays an important role in cell survival and its inhibition leads to apoptosis. Increased monocyte NF-B activity seen in
diabetics with nephropathy than diabetics without nephropathy.70
In vitro studies have demonstrated that high glucose, AGEs, AGN II,
and stretch potently induce NF-B activation mainly via formation of
ROS and activation of PKC7173 providing potential cellular mechanisms of NF-B activation in the diabetic kidney. Recent studies have
shown that NF-B mediates both stretch and high glucose-induced
monocyte hemoattractant protein (MCP) production in mesangial
cells73,74 playing a role in glomerular epithelial cell apoptosis75 and
modulates the TGF-1 intracellular signaling pathway.76 There is thus
preliminary evidence for a role of NFB in the pathogenesis of both
glomerular and tubular damage in diabetes. Both ACE-inhibitor and
statins are potent NF-B inhibitors, and their renoprotective action
may be, at least in part, related to the suppression of NF-B activity.
Conclusion
Diabetic nephropathy develops due to the combined action of both
hemodynamic and metabolic pathways. Metabolic pathways are also
activated within the diabetic kidney and result in accumulation of
AGEs, activation of PKC, renal polyol formation and enhanced oxidative stress. These derangements activate various cytokines and growth
factors. These mechanisms ultimately lead to renal histologic changes
in the glomeruli in DN: mesangial expansion, GBM thickening; and
glomerular sclerosis.
The pathophysiological mechanism of the disease is needed for the
prevention and treatment of DKD. To improve the outcome of DN a
through and scientific knowledge of the complex pathophysiological
aspects is needed.
Acknowledgment
The author wish to thank Dr. K.P. Chintha for helping in preparing the
manuscript and arranging references.
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