Clinical Queries: Nephrology 0102 (2012) 121–126

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Clinical Queries: Nephrology

j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n

Pathophysiology of diabetic nephropathy

P.B. Vinod*
Consultant Nephrologist, Elite Mission Hospital, Thrissur, Kerala, India.

A R T I C L E I N F O A B S T R A C T

Article history: Diabetes is the major cause of chronic kidney disease which in turn may lead to end-stage renal disease
Received 11 February 2012 (ESRD) ending up in dialysis. Hemodynamic and structural changes following diabetes are working together
Accepted 1 March 2012 in the process of development of diabetic nephropathy (DN). Hyperglycemia-induced metabolic and hemo-
dynamic pathways are proven to be the mediators of kidney disease. Hyperglycemia causes the formation of
Keywords: Amadori products, which are the altered proteins and advanced glycation end products (AGE) are the molecu-
Diabetic nephropathy lar players in the phases of DN. According to recent studies, activation of electron transport chain induced
Glomerulosclerosis
by hyperglycemia can result in an increase in the reactive oxygen species (ROS) formation, which is thought
Pathophysiology
Tubulointerstitial fibrosis
to be the initiating event in the development of complications in diabetes. Hemodynamic changes, hyper-
trophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte dam-
age, 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-κB. Transforming growth
factor (TGF)-β 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 approaches.9,11 The recent studies suggest that the insertion or

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.3–5
The present data showing 10 million people with diabetes will dou-
ble by 2030 in the US.6 The financial requirements for maintenance
of dialysis in patients with ESRD due to type 2 DM are higher com-
pared 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 pathophysi-
ological 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 40–50%
of patients with type 1 or type 2 DM will eventually end up in neph-
ropathy.8 The strategies to determine the genetic loci for DN suscep-
tibility 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
deletion polymorphism of angiotensin-converting enzyme (ACE) is
associated only with the progression of the disease and it cannot be
equated as predictor of the development of DN.8 A recent genome
scan for DN in African Americans identified susceptibility loci on
chromosomes 3q, 7p, and 18q.12 Another scan in Pima Indians also
identified linkage to DN on chromosome 7.13 This powerful method
may in the future more clearly identify the genetic risk to develop DN.
Pathophysiology of diabetic nephropathy
The pathophysiological mechanisms in the development of DN are
multifactorial. Hyperglycemia is the initiating event which causes
structural and functional changes such as glomerular hyperfiltration,
glomerular and tubular epithelial hypertrophy, and microalbuminu-
ria, followed by the development of glomerular basement membrane
thickening, accumulation of mesangial matrix and overt proteinuria,
and finally glomerulosclerosis and ESRD.
Hemodynamic pathways
Glomerular hemodynamic changes occurs very early in DN, which
include hyperfiltration and hyperperfusion injuries.14 There is a de-
crease 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 P.B. Vinod / Clinical Queries: Nephrology 0102 (2012) 121–126
Metabolic pathway Hemodynamic pathways
Hyperglycemia High pressure
• AGE • RAAS
• PKC pathway • VEGF
• Polyol pathway • TGF-β
• Oxidative stress • Endothelin
Intracellular signaling molecules and ROS
TGF-β, VEGF, IL-1, IL-6, IL-18, TNF-α
• ECM accumulation
• GBM thickening
• Glomerulosclerosis
Diabetic nephropathy
Figure 1 Pathways involved in the development of diabetic kidney disease. AGE:
advanced glycation end products, IL-1: interleukin-1, IL-6: interleukin-6, IL-18:
interleukin-18, PKC: protein kinase C, RAAS: renin angiotensin aldosterone system,
ROS: reactive oxygen species, TGF-β: transforming growth factor-beta, TNF-α: tumor
necrotic factor-alfa, VEGF: vascular endothelial growth factor.
an increase in glomerular plasma flow.14 Hyperperfusion and hyper-
filtration 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 hemo-
dynamic, 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-β).15 The key role in diabetic
vascular derangement can be attributed to TGF-β. 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 fac-
tors. 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 piv-
otal in this process, linking again structural changes with hemody-
namic 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 in-
terstitial fibrosis.21–25
Increase in extracellular matrix and mesangial cell hypertrophy
causes expansion of the mesangial area which is the earliest mor-
phological 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 ef-
fect 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.26–31
Glomerular basement membrane (GBM) thickening starts as early
as 1 year after onset of type 1 diabetes31 which progresses over the
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
year. Several biochemical alterations of the GBM occur in DN.31 There
is an increase in collagen type IV deposition, whereas the expression
of heparin sulfate and the extent of sulfation decreases. In contrast to
the mesangial matrix in which the α1 and α2 of type IV collagen are
mainly expressed, the GBM contains α3, α4, and α5 chains.32,33 In DN,
there is an up-regulation of α1 (IV) and α2 (IV) chains in mesangial
cells, whereas α3 (IV) and α4 (IV) expression is increased in the GBM.33
Deposition of collagen type I and III in the mesangial area occurs late
in glomerulosclerosis and is not an early event.32
Glomerular epithelial cells (podocytes) directly cover the GBM
and there is recent evidence that alterations in structure and function
of podocytes occur early in DN.34–36 Hyperglycemia causes changes
in integrin expression which influence the podocytes and the GBM
interlinking process.32 Studies in human shows that there is a reduc-
tion in podocyte number on follow-up, related with proteinuria.34
In an European collective of White type 2 diabetics, Vestra et al. found
a significant reduction in the numerical density of podocytes per
glomerulus in patients with type 2 diabetes that were normoalbu-
minuric.37 There is a reduction in the podocyte number in diabetic
patients of all ages, with reduced podocytes per glomerulus even in
short duration of diabetes.38 Podocyte damage occurs before the de-
velopment of glomerulosclerosis and tubulointerstitial damage.39
Metabolic pathways
The glucose transport activity is an important modulator of extracel-
lular 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 glu-
cose transporters (GLUT-4) as well as a brain type of glucose trans-
porters (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 accel-
eration of the polyol pathway along with hemodynamic changes re-
sults in the activation of VEGF, TGF-β, interleukin-1 (IL-1), IL-6 and
IL-18 and tumor necrosis factor alpha (TNF-α). All these pathways
act in unison leading to increased albumin permeability in GBM and
extracellular matrix accumulation, resulting in increasing proteinu-
ria, glomerulosclerosis and finally tubulointerstitial fibrosis.
Oxidative stress
Increase in oxidative stress and the overproduction of reactive oxy-
gen species (ROS) in diabetes is occurring due to hyperglycemia. This
ROS induces peroxidation of cell membrane lipids, oxidation of pro-
teins, renal vasoconstriction and deoxyribonucleic acid (DNA) dam-
age. Various biochemical pathways are also stimulated through the
increased generation of ROS mainly PKC pathways, AGE formation,
TGF-β, and ANG-II.
 P.B. Vinod / Clinical Queries: Nephrology 0102 (2012) 121–126
Hyperglycemia
↑ Mitochondrial ROS
↑ Oxidative stress
↑ Protein kinase C
↑ Sorbitol
↑ Prostanoids
↑ Cytokines
↑ AGEs
NF + κB
Figure 2 Reactive oxygen species as a common mediator of pathophysiological ef-
fects of hyperglycemia. Increased uptake of glucose into cells leads to stimulated mi-
tochondrial reactive oxygen species formation. This oxidative stress, in turn, activates
different processes involving protein kinase C, NF-κB, cytokines, formation of ad-
vanced glycation end products, and others. AGE: advanced glycation end products,
NF: nuclear factor, ROS: reactive oxygen species.
Histopathology of a diabetic kidney specimen shows accumulated
products of glycooxidation and lipooxidation in the expanded mesang-
ial matrix and nodular lesion.
Hyperglycemia results in an increase in mitochondrial ROS for-
mation.42 An increase in glucose uptake leads to overproduction of
electron donors (NADH and FADH 2) from stimulated glycolysis and
the tricarboxylic acid cycle.42 At the mitochondrial inner membrane,
where the electron transport chain is localized, the increase in elec-
tron donors (NADH, FADH 2) generates a high membrane potential
by pumping protons across the inner membrane. As a consequence,
electron transport is inhibited at complex III increasing the half-life
of free-radical intermediates of coenzyme Q, which finally reduces O2
to superoxide.
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. Three-
deoxyglucone which is intermediate, is a precursor of AGEs.43–47
Protein kinase C pathways
An increased flux of glucose through the hexosamine pathway has
also been linked to mechanisms of DN, particularly an increase in
TGF-β.48 Fructose-6-phosphate from glycolysis is converted to glu-
cosamine-6-phosphate in this pathway. Glycosylation of a transcrip-
tion factor such as Sp1 by N-acetylglucosamine stimulates TGF-β
transcription. In addition, an increase in flux through the hexosamine
pathway up-regulates the expression of up-stream stimulatory fac-
tors (USFs) which transactivate the TGF-β1 promoter.49 Intracellular
accumulation of glucose also increases de novo formation of diacylg-
lycerol (DAG) from glycolytic intermediates such as dihydroxyace-
tone phosphate.43 An increase in DAG activates several isoforms of
123
PKC. Inhibition of PKC-β, the major isoform-induced in the kidney by
hyperglycemia, ameliorates DN. Moreover, activation of PKC could,
in turn, further stimulate MAPKs. Erk 1, 2 as well as p38 MAPK have
been implicated as signaling intermediates in DN.43 MAPKs are ad-
ditionally activated by ROS and there is likely cross-talk between the
various pathways.44 The importance of PKC in the development of
some changes of DN is underscored by recent studies demonstrating
that albuminuria was absent in diabetic PKC-α knockout mice.50
However, glomerular hypertrophy or the up-regulation of TGF-β was
not influenced by the lack of PKC-α.50
Advanced glycation end products
In longstanding hyperglycemia, the excess glucose combines with
free aminoacids or tissue proteins. This glycosylation leads to the
development of DN. This process initially forms reversible early gly-
cosylation products and later irreversible AGE. The matrix proteins in
the glomerular epithelial cells get accumulated along with decrease
in collagenase activity and defect in the glomerular epithelial cell
tight junction, because of the increase in AGEs.51
Cytokines and growth factors
Various growth factors, cytokines, chemokines, and vasoactive agents
have been implicated in structural changes of DN.52–56 Insulin-like
growth factors (IGFs) are among the most widely and earliest studied
growth factors in DN but the exact role remains elusive.57 An early
and temporary increase in renal IGF-I protein after the onset of dia-
betes is found in various animal models and this increase is caused
by hyperglycemia.57 Interference with the IGF-I axis partly attenuates
DN in some models.52
Transforming growth factor-b references changes
Transforming growth factor-β is a profibrotic growth factor causing
the expansion of mesangial matrix and renal hypertrophy in DN.58
High levels of TGF-B have been measured in the glomeruli of strpto-
zotocin diabetic rats.59 It was reported that neutralizing TGF-β anti-
body prevented diabetic renal atrophy, mesangial matrix expansion,
and the development of renal failure in type 2 db/db mice.60 Connec-
tive tissue growth factor and heat shock proteins, which are encoded
by TGF-β, have fibrogenic effects on the kidneys of patients with dia-
betes. However, the profibrogenic actions of TGF-β1 are countered
by the decreased expression of renal bone morphogenic protein 7.61
Mechanical stretch induces both gene and protein expression of TGF-
β1.62 Stretch, via the intracellular signaling molecule protein kinase C,
causes early activation of p38 mitogen-activated protein kinase, which
induces TGF-β1 and fibronectin production.63 The TGF-β1 contributes
to the cellular hypertrophy and increased synthesis of collagen,
which inturn leads to DN.64,65 The platelet derived growth factor-beta
(PDGF-β) cause histological alterations in the glomerulus. Hypergly-
cemia up-regulates PDGF-β growth factor and its receptor in the
mesangial cells leading to enhanced TGF-β expression.66
Vascular endothelial growth factor
Overexpression of VEGF induces diabetic renal disease by increasing
the permeability of vascular endothelium, endothelial cell prolifera-
tion and migration, reducing transendothelial electrical resistance, and
activation of matrix-degrading protease.67,68 Synthesis of endothelial
nitric oxide which causes vasodilatation and hyperfiltration is in-
duced by hyperglycemia, TGF-β1, ANG-II, and VEGF overexpression.
The VEGF overexpression causes increased production of collagen chain
contributing to the increased thickening of GBM DN. Some studies
refute causative role for high VEGF levels in DN. Instead, results imply
that low levels are harmful. Baelde et al showed that VEGF messenger
124 P.B. Vinod / Clinical Queries: Nephrology 0102 (2012) 121–126
ribonucleic acid (RNA) concentrations were decreased in the glomeruli
of patients with DN and correlated with reduction in the number of
podocytes and progression of renal disease.69
Intracellular signal pathways
Nuclear factor-kB
Nuclear factor-κB plays an important role in cell survival and its inhi-
bition leads to apoptosis. Increased monocyte NF-κB 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-κB activation mainly via formation of
ROS and activation of PKC71–73 providing potential cellular mecha-
nisms of NF-κB activation in the diabetic kidney. Recent studies have
shown that NF-κB 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-β1 intracellular signaling pathway.76 There is thus
preliminary evidence for a role of NFκB in the pathogenesis of both
glomerular and tubular damage in diabetes. Both ACE-inhibitor and
statins are potent NF-κB inhibitors, and their renoprotective action
may be, at least in part, related to the suppression of NF-κB activity.
Peroxisome proliferator-activated receptor-g
Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear
transcription factor and the pharmacologic target for the insulin sen-
sitizers known as thiazolidinediones (TZDs). Preliminary studies sug-
gest that TZDs may ameliorate urinary albumin excretion in type 2
diabetic patients with microalbuminuria.77 Moreover, TZDs have an-
tiproteinuric effects independent of their insulin-sensitizing action
in rats with streptozotocin-induced diabetes.78,79 The underlying mech-
anism of this protective action is still unclear. In diabetic glomeruli
and mesangial cells exposed to high glucose there is a strong down-
regulation of PPAR-γ80 and PPAR-γ ligands may counterbalance a
PPAR-γ relative deficit in diabetes. Furthermore, recent in vitro stud-
ies have shown that PPAR-γ ligands prevent production of both TGF-
β1-induced collagen type 180 and stretch-induced MCP-1, providing a
potential link between PPAR-γ deficiency and glomerulosclerosis.
Hypoxia and diabetic nephropathy
In patients with diabetes nephropathy, anemia accelerates the pro-
gression of pathophysiology.81 Early treatment with erythropoietin
slows down the renal disease progression.82–83 Renal hypoxia result-
ing from anemia aggravates interstitial fibrosis by the stimulation of
factors like TGF-β and VEGF.84 Hypoxia-inducing factor-1 (HIF-1), and
ANG-II also plays a major role in this.85
Inflammation and diabetic nephropathy
Inflammatory cells like mononuclear cell infiltrate are often found
in the glomerular and tubular compartments on biopsy.86,87 Hyper-
glycemia increases expression of MCP-1 in mesangial cells and RANTES
and MCP-1 in tubule.87–91
High glucose leads to the generation of ROS and increases AGE
synthesis. Reactive oxygen species stimulate local ANG-II generation,
which increases proteinuria, but proteinuria also further enhances
tubular ANG-II synthesis. Angiotensin-II also increases AGE formation
and is pivotal in the induction of various cytokines and growth fac-
tors. Some of these cytokines directly stimulate extracellular matrix
synthesis (e.g., TGF-β, CTGF), whereas other mediate inflammation
(MCP-1). As a consequence of these processes, tissue destruction and
fibrosis results.92,93
The proteinuria in combination with hyperglycemia and AGEs in-
creases the expression of chemokines in podocytes and tubular cells.
High glucose
ROS
AGEs ANG-II Proteinuria
Cytokines (TGF-β, VEGF, MCP-1)
Inflammation
Tissue destruction fibrosis
Figure 3 Summary of mediators involved in the pathophysiology of diabetic nephro-
pathy. AGE: advanced glycation end products, ANG-II: angiotensin-II, MCP: monocyte
hemoattractant protein, ROS: reactive oxygen species, TGF-β: transforming growth
factor-beta, VEGF: vascular endothelial growth factor.
The proinflammatory transcription factor NF-B was detected mainly
in tubular cells in biopsy specimens from 11 patients with type 2 dia-
betes and overt nephropathy, indicating that proteinuria may have
contributed to this activation.94 Proteases released by the mononu-
clear cells and cytokine such as TGF-β, leads to permanent damage to
nephron in DN. The ANG-II also induced the production of proinflam-
matory cytokines.87
Role of the renin–angiotensin–aldosterone system
Zatz et al have shown that ACE-inhibitor prevented the development
of nephropathy in experimentally induced diabetes.92 Inhibition of
renin–angiotensin–aldosterone system (RAAS) causes normalization
of systemic and glomerular hypertension and also anti-fibrotic and
anti-inflammatory actions (Figure 3).93 The increase in local ANG-II
concentrations mediated by the hyperglycemia-induced overexpres-
sion of rennin and angiotensinogen in mesangial and tubular cells
which may in turn induce the production of variety of cytokines and
growth factors.93–97 Inhibition of the RAAS reduces proteinuria in DN.
Nehrin expression in podocytes suppressed by an increase in ANG-II.
The proteinuria and trasit of proteins through the ultrafiltration
barrier and also mechanical stretch stimulates ANG-II formations in
podocytes.98,99 Chymase, an ANG-II-forming enzyme not inhibited
by ACE inhibitors, is up-regulated in glomeruli of patients with ne-
phropathy owing to type 2 diabetes.100 The suppression of nephrin
expression and the resulting enhanced ultrafiltration of proteins
can be attributed to the local increase in ANG-II concentration in
the podocytes.
It is seen that ANG-II increases tubular reabsorption of proteins
leading to tubular inflammation and fibrosis. Aldosterone also has a
role in the development of DN. The aldosterone antagonist spironol-
actone caused increased collagen deposition in rats 3 weeks after
streptozotocin administration. The TGF-β1 expression was also sup-
pressed by spiranolactone this model.93–97 These findings have been
extended to patients. In a preliminary study, Schjoedt and colleagues
observed that an increase in the plasma aldosterone level during
long-term treatment with an AT1-receptor blocker (aldosterone es-
cape phenomenon) is associated with a decline in glomerular filtra-
tion rate in patients with nephropathy owing to type 1 diabetes. These
data demonstrate that aldosterone contributes to the progression
of DN despite blockade of the AT1-receptor.101 On the other hand,
spironolactone decreases proteinuria in patients with 2 diabetes and
early nephropathy.102 The newer antagonist of aldosterone eplerenone
reduces microalbuminuria in diabetes.103 the progression to full blown
DN can be prevented by timely treatment with drugs interfering
with the RAAS.
 P.B. Vinod / Clinical Queries: Nephrology 0102 (2012) 121–126
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 oxida-
tive 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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