Download - Paper - Pathogenesis of Diabetic Nephropathy
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
1/12
Reviews in Endocrine & Metabolic Disorders 2004;5:237248C 2004 Kluwer Academic Publishers. Manufactured in The Netherlands.
Pathogenesis of Diabetic NephropathyClaudia van Dijk and Tomas Berl
University of Colorado Health Sciences Center, Division of Renal
Diseases and Hypertension, 4200 E. 9th Ave., C-281, Denver, CO
80262, USA
Key Words. diabetes, kidney disease, mechanism
Introduction
Diabetes Mellitus (DM) is the most common cause of
end-stage renal disease (ESRD) across racial and ethnic
groups in the United States (US) and other developed
countries. According to most recent USRDS reports, dia-
betic nephropathy (DMN) represents 44% of new cases of
ESRD in theUnited Statesand accounts forfar higherrates
in black, Native American and Hispanic populations than
it does in whites. The incidence of diabetic nephropathy
(DMN) continues to rise far more rapidly than rates due to
any other primary diagnosis of ESRD as a result of the in-
creasing prevalence of DM, predominantly thosewith type
2 diabetes (T2DM) [1]. A total of 131,173 patients with
DMN were requiring renal replacement therapy: 77% of
these were on hemodialysis, 6.2% are on peritoneal dial-
ysis and 16.1% are transplant recipients according to the
2002 data report.
ESRD is associated with high mortality rates, and
among these, those with DMN have the highest rates. Ad-
justed relative risk of death in diabetic dialysis patients
compared to their non-diabetic counterparts was 1.69 in a
large cohort study [2]. The high mortality rates in the pre-
dialysis period in these patients may underestimate the
poor progression that the diagnosis of diabetic nephropa-
thy imparts [3].
Predisposing Factors for the Development
of Diabetic Nephropathy
As was summarized by Ritz and Orth [4], the risk factors
associated with the development of DMN in the diabetic
population include older age, non-caucasian race, male
sex and poor glycemic, lipid and blood pressure controls.
Genetic patterns have been established with familial
occurrences of DMN and associated hypertension and
cardiovascular diseases in family members of patients
with DMN [5]. A clustering of DMN in some families
with IDDM and NIDDM has lead to the belief that a
genetic susceptibility predisposes to development of
ESRD. Cumulative risk increase of DMN from 25 to
72% has been observed if the index case in a diabetic
family had persistent proteinuria. Linkage to at least one
major gene on chromosome 3q, in vicinity of the AT1
locus, has been observed, and polymorphisms in the
angiotensinogen and angiotensin-1 converting enzyme
genes appear to make minor contributions [6]. A genetic
defect in regulation of glycosaminoglycans production by
endothelial and mesangial cells has also been correlated
with susceptibility of diabetics to progress to DMN [7].
Pathophysiology of Hyperfiltration
and Diabetic Nephropathy
Although the pathogenesis of type 1 and type 2 DM
is different, the pathophysiology of microvascular com-
plications responsible for high morbidity and morality
rates appears similar. Hyperglycemia underlies microvas-
cular complications in all end-organ tissues and is at
least partially responsible for glomerular hyperfiltration
in DMN (Fig. 1). A very common pathologic feature of
early DMN is the presence of glomerular hypertrophy,
with mesangial expansion and glomerular basement mem-
brane thickening. Likewise, the early hemodynamic al-
terations include both low afferent and efferent arteriolar
resistance, a markedly increased plasma flow, a moder-
ately increased glomerular capillary pressure leading to
an increased glomerular filtration rate (GFR). This earlystage of hyperfiltration precedes the eventual deteriora-
tion of renal function. While the hyperfiltration and hy-
pertrophy are at least in part markers of poor glycemic
control, the pathogenetic contribution of hyperfiltration
to the ultimate loss of renal function is not fully defined
[8].
The impact of numerous hormonal and vaso-active
factors in the pathogenesis of the hyperfiltration in
early stages of DM has been evaluated as to their
E-mail: [email protected]
237
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
2/12
238 van Dijk and Berl
Fig. 1. Pathophysiology of hyperfiltration.
role. Prostaglandins, thromboxane, kalikrein and nore-
pinephrine all do not appear to be associated with in-
creases in GFR [8]. Findings of elevated atrial natriuretic
peptide (ANP), fluid and sodium retention as a conse-
quence of sodium-coupled reabsorption by the brush-
border co-transporters in the proximal tubule [9], and re-
duced renin-angiotensin-aldosterone system (RAAS) ac-
tivity appear to be associated with induction of hyper-
filtration in diabetics with poor glycemic control [8,9].
Some of these changes may be related to the volume ex-
pansion in the hyperglycemic state (secretion of ANP andin inhibition of the RAAS). A direct vasodilation medi-
ated by the osmotic effect of hyperglycemia or sorbitol-
induced activation of the polyol pathway has also been
implicated.
Insulin appears to ameliorate hyperfiltration by both
reducing hyperglycemia and by causing systemic vasodi-
latation that can concomitantly reduce blood pressure. In
this regard the effect of insulin on mesangial cell con-
tractility has been extensively investigated [1012]. These
effects are independent of changes in renin, aldosterone
or catecholamines. Impaired calcium uptake by vascular
smooth muscles and impaired contractile response to an-giotensin II in insulin deficient states was noted in vitroin
such cells, as well as in the evaluation of the hormones
contribution to hyperfiltration in animal studies [10,12].
A primary tubular ratherthan a vascularmechanism has
also been postulated. In this conception it is an increase
in reabsorption of sodium in proximal tubules that causes
GFR to increase by the physiologic action of the tubulo
glomerular feedback (TGF) [13]. The role of an arginine
ornithine polyamine pathway has been implicated in both
proximal tubular reabsorption and enlargement of the
diabetic kidney. Use of difluoromethylornithine (DFMO),
an inhibitor of the polyamine synthetic enzyme ornithine
decarboxylase reduced reabsorption and filtration in
diabetic rats along with attenuation of renal growth [13].
Use of DFMO to ameliorate DMN must therefore be
considered and investigation of this pathway is ongoing.
A growing body of information indicates that vascular
endothelium plays an important role in the regulation of
smooth muscle tone and subsequent filtration. Production
of substances known to influence vascular tone, such
as endothelin and nitric oxide (NO), is altered under
diabetic conditions causing an imbalance that may be
at least partially responsible for the development of
hyperfiltration [14,15]. Defective endothelial NO (eNOS)has been implicated to play a role in the pathogenesis of
hyperfiltration. However, all isoforms of NO have been
found to have significantly increased cortical but not
medullary expression in streptozotocin (STZ)-induced
diabetic rats [16]. A possible role for neuronal NO
(nNOS) to counteract afferent vasoconstiction induced
by TGF has been postulated [17,18].
As noted above, nephromegaly is a commonly de-
scribed feature in early diabetic changes in association
with hyperfiltration. It is a poor prognostic factor for de-
velopment of DMN [19]. Whether the development of
nephromegally is a direct consequence of hyperfiltrationdue to a compensatory state similar to that seen after uni-
lateral nephrectomy, is questioned in studies shown to
ameliorate hyperfiltration but not kidney size during strict
glycemic control [20,21]. The above mentioned tubu-
loglomerular feedback mechanism argues that increased
tubular reabsorption spurs filtration and results in ini-
tial kidney growth. Growth factors such as GH, IGF,
EGF, TGF and PDGF have been implicated in numer-
ous reports, with upregulation of their genes and proteins
noted in the diabetic kidney [22,23]. It must be noted
that nephromegaly predominantly reflects tubulointersti-
tial changes, accounting for more than 90% of kidney
mass.
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
3/12
Diabetic NephropathyPathogenesis 239
Development of DMN; A Glomerular
and Tubulointerstitial Process
A dissociation between glomerular injury and renal dys-
function prompted a shift of focus from glomeruloscle-
rosis, with albuminuria and mesangial expansion, to the
tubulointerstitial compartment with a strong correlation
between the degree of tubulointerstitial damage and renal
function [24]. It is increasingly recognized that tubuloin-
terstitial changes are not simply a downstream reflection
of glomerular damage, as evidenced by the high number
of atubular glomeruli in progressive diabetic nephropathy
[25]. Pathological examination of a large cohort of dia-
betics with microalbuminuria showed that 29% had typi-
cal DMN including balanced severity of glomerular scle-
rosis, arteriolar hyalinosis and tubulointerstitial changes.In contrast 42% displayed predominant tubular atrophy
and interstitial expansion [26]. Patients with patholog-
ical changes had significantly worse glycemic control
as evidenced by elevated HbA1C, but interestingly high
prevalence of proliferative retinopathy occurred mainly
in the group with typical diabetic glomerular changes.
Glycemic, hypertensive and aging factors could all con-
tribute to a varying picture of pathologic changes. Mecha-
nisms proposed by which non-glomerular renal dysfunc-
tion occurs may be related to simultaneous exposure of
prosclerotic cytokines in glomeruli and tubulointerstitium
and to the tubulotoxicity caused by the protein contentsin filtrate overloading the proximal tubules reabsorptive
ability, which is the predominant site of tubular damage
[27]. Increased filtered plasma protein reaches the proxi-
mal tubule in the diabetic kidney characterized by abnor-
mal permeability. Resultant endocytosis of these proteins
by tubular epithelium exceeds lysosmal capacity when
large quantities of protein are present in the filtrate. Rup-
ture of lysosomes and phenotypical transformation of ep-
ithelial cells to release endothelin and chemotactic factors
results. Potent vasoconstriction and chemotaxis then leads
to inflammation, ischemia and ultimately fibrosis, espe-
cially in most heavily burdened region such as proximal
tubules and surrounding interstitium [26].Finally, a postglomerular vasoconstriction has been
postulated to occur with hyperglycemia which may re-
sult in tubular ischemia and degeneration. The tubular
ischemia leads to further interstitial leak of glomerular
filtrate resulting in interstitial fibrosis [28]. A contribution
of angiotensin II to tubulo-interstitial injury has also been
proposed [29].
Microalbuminuria/Proteinuria
Lifetime risk of persistent proteinuria is 33%in type 1 DM,
with a peak incidenceduring seconddecade of IDDM [30].
Dependence on insulin had a significant influence on the
risk of progression to overt nephropathy once microal-
buminuria was diagnosed in a 10 year follow-up study
[31]. Proteinuria was found to be a powerful predictor ofshortened survival in patients with both type 1 and 2 DM
[32]. This likely reflects the correlation between microal-
buminuria and vascular complications. When detected in
early stages, a more recent study has shown that regres-
sion of microalbuminuria is feasible, and this correlates
with preservation of renal function [33].
Proteinuria occurs as a result of abnormal charge
permselectivity. This occurs due to reduction in glomeru-
lar charge density as a consequence of non-enzymatic gly-
cosylation of various basement membrane proteins and
altered glycosaminoglycan (GAG) metabolism leading to
reduced heparan sulfate content. GAG administration inanimal models of diabetes has been shown to exert an
antiproliferative and antimitogenic effect on glomerular
epithelial cells and increases negative electrical charge of
the endothelium [34].
The association between high protein diet and deterio-
rationof renal function is controversial andstudiesdone on
varying cohorts of patients infrequently included diabet-
ics. Due to differences in design, sample size and methods
used to assess progression of renal disease, studies have
inconsistently shown the beneficial effect of dietary pro-
tein restriction [35]. Pooled results suggest significant re-
duction of decline in GFR and urinary albumin excretion
as well as death in protein restricted patients. An initial
reduction in single-nephron GFR was observed with sub-
sequent slowing of progression of renal disease in several
studies while other reports show correlation between pro-
tein intakeand GFR, but not with albuminuria [36]. Evalu-
ation of potential benefits of reduction of proteinuria with
ACE-I therapy while maintaining normal-to-high protein
intake in order to provide adequate nutritional support,
has not been tested in humans. Animal studies showed a
significant reduction in albuminuria during high protein
intake with concomitant use of ACE-inhibition. Based on
currently available data the recommended dietary protein
intakeranges between 0.50.8 gm/kg of body weight, withapproximately 65% as high biological value protein and
caloric intake sufficient to maintain body weight.
Hypertension
Hypertension and diabetes are co-morbid conditions with
a nearly 100% correlation, associated as part of the
metabolic syndrome which is growing in endemic pro-
portions [37]. Increased incidence of atherosclerosis and
association with left ventricular hypertrophy and diastolic
dysfunction in the diabetic population has led to the de-
scription of a diabetic cardiomyopathy. Many previously
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
4/12
240 van Dijk and Berl
published reports have observed the renoprotective effect
of blood pressure reduction [38,39] leading to more ag-
gressive recommendation for blood pressure control in di-
abetics, aiming for a target of less than 130/80 (JNC VII)[40]. Independent benefits are shown with angiotensin-
converting enzyme-inhibitors (ACE-I) and angiotensin re-
ceptor blockers (ARB) for rate of loss of renal function,
time to ESRD, stabilization of microalbuminuria, regres-
sion to normoalbuminuria, and even for some cardiovas-
cular outcomes and mortality for any given blood pres-
sure [4143]. Non-hemodynamic benefits of these agents
are likely underlying these observations. The role of an-
giotensin receptor 1 (AT1) versus AT2 blockade and newer
agents such as vasopeptidase inhibitors are currently un-
derinvestigation[44,45]. In this review, we will not further
discuss the RAAS system and its hemodynamic effects asthis has been extensively covered in the aforementioned
published reports [3843].
Non-Hemodynamic Mechanisms of DMN
Role of advanced glycosylation endproducts(AGEs)Accumulation of nonenzymatically derived glycosylation
products on proteins, lipids and amino acids results in
formation of Amadori products. These products of a cova-
lent, nonenzymatic Maillard reaction include circulating
and tissue-structure proteins such as arterial-wall collagen
and glomerular basement membrane proteins. Conversion
of these Amadori proteins over months and years into
AGEs with highly cross-linked nature, responsible for
pathogenesis in diabetic complications, appears to occur
more rapidly in tissues of diabetic patients compared to a
similar phenomenon in aging [46,47]. Markedly increased
circulating levels of AGE peptides were noted in diabetics
with ESRD in a study comparing serum AGE levels to
Fig. 2. Advanced glycosylation endproducts pathway.
their diabetic counterparts without renalinvolvement [48].
Accumulation of AGEs is characteristic of DMN, particu-
larly in the mesangium and in nodular lesions. Staining for
renal specific AGEs was reported to correlate with severityof DMN in human diabetic subjects [49].
Extracellular matrix proteins, known to have a low
turnover, are easily susceptible to AGE modification with
formation of inter- and intracellular cross-links. The for-
mation of crosslinks is responsible for structural changes,
including increased stiffness and density and decreased
thermal stability, resistance to proteolytic degradation and
loss of epithelial phenotype. Changes in cellular adhesion
and decreased affinity of laminin and fibronectin for type
IV collagen and heparin sulfate proteoglycan result in al-
tered protein permeability [50]. The prevention of AGE
formation as well as inhibition of AGE-induced crosslinkshave shown to prevent the occurrence of albuminuria,
confirming the importance of proposed mechanism in the
pathogenesis of DMN [51]. Modification of lipoproteins
(apo-B and LDL) resulting in their delayed clearance, en-
hanced oxygen radical formation with subsequent nuclear
factor-B (NFB) activation and cell proliferation or pro-
grammed cell death are consequences of AGE accumula-
tion believed to be implicated in pathogenesis of diabetic
complications (Fig. 2).
RAGE, a receptor for AGE that is present on
macrophages, is a member of the immunoglobulin super-
family. RAGE is responsible for the clearance of AGE-
modified proteins. Renal clearance of breakdown prod-
ucts is ultimately responsible for elimination; therefore
the presence of renal insufficiency leads to a signifi-
cantly increased plasma and tissue levels of AGEs and
its breakdown products [48]. The accumulation of circu-
lating AGEs is directly related to extent of remaining renal
function and may further contribute to a more rapid dete-
rioration towards ESRD.
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
5/12
Diabetic NephropathyPathogenesis 241
Balance of AGE/RAGE system. Various receptors for
AGE have been identified on multiple cell types. The
most extensively described receptor is RAGE. Affinity for
AGEs with fondness for accumulation in renal tissue (N-carboxymethyllysine (CML) and pentosidine) to RAGE
suggest importance of this receptor in the development
of nephropathy. Studies have shown correlation of CML
and pentosidine with glomerular lesions in both diabetic
and non-diabetic renal disease; only in diabetic conditions
however did this seem to be associated with upregula-
tion of RAGE [49]. It seems therefore that the balance of
AGE/RAGE system especially in diabetes becomes one of
the predominant factors to consider in pathogenesis of re-
nal disease. Interactions of AGEs with RAGE to generate
reactive oxygen species (ROS) have been implicated as a
mechanism underlying these findings [52]. Activation of arange of second messenger systems and increased produc-
tion of cytokines including TGF, PDGF and IL-1 have
also resulted from interaction between AGEs and RAGE.
AGEs and tubular-epithelial myofibroblast transdif-
ferentiation. The occurrence of transdifferentiation of
tubuloepithelial cells into mesenchymal phenotype is
observed and felt to be mediated through RAGE in a
TGF-dependent fashion [53]. Activation of NFB and
protein kinase C (PKC) is mediated through AGE in a
self-sustaining mechanism. Binding sites of NFB arepresent on RAGE and this binding lowers the threshold
for AGE to induce NFB during anti-oxidant depletion
[54,55]. Exposure of proximal tubules to high levels of
AGE-peptides due to active reabsorption in this portion
of the nephron and interaction with RAGE which have
shown to be distributed at this site [56], could explain the
phenomenon of tubular-epithelial myofibroblast transdif-
ferentiation (TEMT).
AGEs and oxidative stress. Induction of endothelial dys-
function as the result of accumulation of AGEs withdefective vasodilatation and reduced NO predisposes to
vascular complications. This process is further enhanced
by monocyte chemotaxis, adhesion-molecule expres-
sion, decreased prostacycline formation and plasminogen-
activator inhibitor-1 (PAI-1) induction [57]. AGE-induced
increase in oxidative stress has beendemonstrated in DMN
and ESRD [58] and attenuation of mitochondrial super-
oxide production leads to diminished AGE accumulation
pointing out the self-perpetuating mechanism of the devel-
opment of DMNtrough oxidative andglycation pathways.
Blockage of AGEs with aminoguanidine was equally ef-
fective to ACE-I in animal models of diabetes to reduce
proteinuria and tubular as well as glomerular nitrotyrosine
levels to control levels,suggesting notonly theimportance
of binding of Amadori compounds but also an additional
blockade of inducible nitric oxide synthase and free oxy-
gen radical propagation in the prevention of DMN [59].
Animal studies. As described in previously mentioned
experiments, AGEs has been implicated in the patho-
genesis of DMN. Various mechanisms by which AGEs
contribute to the occurrence of renal disease have been
postulated including aforementioned interactions with its
receptors, enlisting various growth and transcription fac-
tors, cytokines and oxidative stress pathways as its mayor
players. Induction of profibrotic cytokines and growth fac-
tors, with increased expression of laminin and type IV
collagen after AGE-injection into animals independentof glycemic control, leads credence to the existence of
an AGE-mediated mechanism of fibrogenesis [60]. In-
traperitoneal administration of AGE to normal SJL mice
enhanced 1 type IV collagen, laminin B1 and TGF
mRNA. These effect where abolished by co-treatment
with aminoguanidine, an AGE-inhibitor, further implicat-
ing AGE in causal relationship between AGE accumu-
lation and renal injury [61]. Longterm exposure of rats
to AGE albumin through tail vein injections resulted in
doubling of plasma AGE levels and fourfold increase of
urinary and kidney contents of AGE. These biochemical
changes correlated with increase of glomerular volume,
widening of basement membrane, expansion of mesangialmatrix and proteinuria. Deleterious effects on the vascular
system were also noted.
Human data. Evidence of TEMT (tubular-epithelial
myofibroblast transdifferentiation) was noted on renal
biopsies of humans with IDDM by positive immunostain-
ing of-smooth muscle actin (-SMA) in tubular epithe-
lial cells in early stages of nephropathy. Co-localization of
AGE andRAGE in a Kimmelstiel-Wilson lesions of a post-
mortem kidney further provides a potential pathogenic
mechanism for development of tubulo-interstitial fibro-
sis [53]. The presence of TGF in human specimens
in association with TEMT however, has not yet been
confirmed.
Role of reactive oxygen species (Fig. 3)Hyperglycemia induces vascular injury through complex
overlapping pathways including enzymatic and nonenzy-
matic processes including formation of AGE, activated
PKC and reactive oxygen species (ROS). The effect of
anti-oxidant therapy in cell and animal studies strongly
suggest an important role for ROS in theinitiation andpro-
gression of DMN [62]. Lack of occurrence of nephropa-
thy in normoglycemic insulin-resistant patients, where
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
6/12
242 van Dijk and Berl
Fig. 3. Reactive oxygen species pathway.
increased superoxide production also is observed, along
with paucity of evidence for beneficial anti-oxidant effects
in humans may, however, suggest a supportive but not
initiating role for ROS [63]. Reducing equivalents result-
ing from glycolytic process in the metabolism of glucose
drive the synthesis of adenosine triphosphate via oxidative
phosphorylation in mitochondria (Fig. 3). Byproducts of
this mitochondrial oxidative phosphorylation include free
radicals. As a result of the abnormal metabolic milieu in
DM (hyperglycemia, hyperlipidemia and increased FFA)
ROS are thought to be increased. Increased production
of glyco-oxidants, glycated compounds, oxidized LDL,superoxidants, nitrotyrosine and elevated levels of iso-
prostanes, 8-hydroxydeoxy- guanosine and lipid perox-
ides have been reported in cell, animal and human studies
(reviewed in [62] Glucose auto-oxidation also results in
free radical formation. Increases in oxidative stress dam-
ages cellular proteins and promotes leukocyte adhesion
to the endothelium while inhibiting its barrier function
[64,65].
H2O2 is increasingly recognized as an intracellular
messenger produced in response to receptor stimulation.
Propagation of its signal occurs by oxidizing cysteine
residues in active sites of protein tyrosine phosphatase.The function of various proteins including protein ki-
nases and transcription factors can be altered through
oxidation of their H2O2-sensitive cysteine residues [66].
Pathways affected by overproduction of superoxide in-
clude the polyols, AGEs, PKC, TGF and NFB, all
of which are known to mediate vascular damage in
diabetics.
An antioxidant defense system is employed in
healthy cells that includes ROS scavengers such as uric
acid, ascorbic acid, catalase, glutathione, glutathione
peroxidase and superoxide dismutases. In pathologic
circumstances failure of this scavenger system occurs
due to overwhelming production of ROS. Irreversible
modification of biologic macromolecules and altered NO
bio-availability can lead to inflammation, endothelial
dysfunction, fibrosis and apoptotic cell death. Resultant
clinical syndromes include hypertension, renal disease
and accelerated atherosclerosis.
Animal studies versus human data. Major enzymatic
sources of ROS generation are NADPH oxidases of the
nonphagocytic cell types such as endothelial cells, vas-
cular smooth muscle cells, renal mesangial and tubu-
lar cells among others [67,68]. In response to a varietyof hormones, growth factors, cytokines and mechanical
stress as well as its own end-product ROS, NADPH ox-
idase can regulate signaling of ROS into a cascade of
oxidative damage. A study on human arterial contents
of NADPH oxidase reported marked elevations in car-
diovascular risk groups compared to controls. Diabetes
and hyperlipidemia were independently associated with
NADPH oxidase-derived ROS generation in this study
[69]. Elevated levels of markers of oxidative stress such
as urinary isoprostanes and oxidized low-density lipopro-
tein cholesterol also have been reported in diabetic pa-
tients [70]. Besides the mulitfactorial sources of ROS,a renal derived NADPH oxidase termed renox has been
shown to be expressed in renal parenchyma. This pro-
vides a local source of ROS to renal tissue, which is vul-
nerable to oxidative damage [68]. Only small amounts
of ROS are generated in healthy renal mesangium and
tubular cells. Animal studies suggest a role for the consti-
tutively active NADPH oxidase leading to ROS produc-
tion under normal physiologic conditions in regulation of
medullary blood flow and arterial pressure. Under exces-
sive oxidative stress this may lead to renovascular hyper-
tension [71]. Modulation of local ROS production in renal
parenchyma may be a promising step in the prevention of
DMN.
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
7/12
Diabetic NephropathyPathogenesis 243
Fig. 4. Polyol pathway.
Role of the polyol pathwaySubstantial contributions of the polyol pathway are pos-
tulated in addition to previously discussed effects from
glycated products and their receptors to induce oxidative
stress as a result of hyperglycemia. The polyol pathway
consists of aldose reductase (AR) which reduces glucose
to sorbitol with the aid of co-factor nicotinamide adenine
dinucleotide phosphate (NADPH), and sorbitol dehydro-
genase (SDH) with co-factor NAD+, responsible for con-
version of sorbitol to fructose (Fig. 4). Under normal phys-
iologic conditions only a small amount of glucose is han-
dled through this pathway; however, significant increases
from 3 up to 30% can be seen in the diabetic state. Cellu-lar accumulation of sorbitol and depletion of myoinositol
have been documented to happen selectively in tissues
predisposed to developing diabetic complications, includ-
ing the kidney [72]. Prevention of some of the pathologic
changes in animal models of diabetic nephropathy as well
as other diabetic complications by inhibition of the polyol
pathway points out the importance of this enzyme system
in the pathophysiology in DMN [7375].
Mechanisms by which polyols contribute to the occur-
rence of diabetic complications in addition to induction
of oxidative stress possibly include osmotic-induced vas-
cular damage through accumulation of sorbitol and freeradical scavenging functions. The poylol pathway plays a
role in the induction of oxidative stress in several ways.
Due to channeling of glucose into the polyol pathway un-
der hyperglycemic conditions, a significant depletion of
NADPH, co-factor to AR, causes a diminished regen-
eration of glutathione (GSH) by glutathione reductase
(Fig. 4). Reduced GSH stores are then responsible for de-
creased antioxidant properties in the defence against ROS.
In addition SDH activity under hyperglycemic conditions
shunt NAD+ into substrate for the reaction of NADPH
oxidase to form ROS. Also, fructose and its metabolites
whenglycosylated are more potent glycation end-products
fueling AGE-induced oxidative stress [76]. Increase flux
through the pentose phosphate pathway (PPP), by deplet-
ing its inhibitor NADPH and by oxidative reactions, al-
tering the NADH/NAD+ratio further promotes oxidative
stress [77].
Animal data versus human studies. The fact that mice
tend to have low levels of aldose reductase and diabetic
mice appear to be resistant to the development of cataract,
raised the question of polyol-induced damage to end-organ
tissues common to human diabetic disease. Transgenic
mice studies leading to overexpression of AR in combina-
tion with streptozocin (STZ)-induced diabetes resulted in
development of cataracts [78]. Evidence for increases ofoxidative stress in lenses of mice who developed cataract
suggest that AR contributes to diabetes-associated oxida-
tivestress. Similar findings of a role forAR in theinduction
of diabetic neuropathy has been described. The role of AR
in development of DMN has been studied extensively in
the last decade as well.
AR expression in rats predominates in the inner stripe
of the outer medulla, the inner medulla and at the papillary
tip. Relatively less expression of AR can be observed in
the outer medulla and cortex, both in mesangial and prox-
imal tubule cells as evidenced by accumulation of sorbitol
and fructose [79]. Increases in AR mRNA in rat mesangialcells in response to elevated glucose levels and increased
renal AR gene expression in STZ-induced diabetic rats
implicate that hyperglycemia stimulates AR gene expres-
sion [80]. The effect of hypertonicity was suggested to be
the mechanism by which hyperglycemia may influence
AR gene expression by activation of the osmotic response
element (ORE). Glucose, however, more so than other os-
molytes at both markedly and mildly hyperglycemic con-
ditions was able to alter AR gene expression [81].
In humans, a genetic variation in the AR gene (ALR2)
of patients with type 1 DM has been shown, which may
contribute to the genetic susceptibility to DMN [82].
Emerging interest in the polyol pathway as a potential
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
8/12
244 van Dijk and Berl
target for modification of diabetic complications also fol-
lows from findings of increased AR mRNA expression
in patients with DMN compared to type 1 DM with-
out nephropathy suggesting that the degree of AR geneexpression can modulate risk for development of DMN
[83]. Controversy however surrounding the contribution
of AR in DMN is the result of lack of efficacy of AR
inhibitors in human trials. Findings of reduced hyperfil-
tration and/or progression of microalbuminuria in some
human trials are contradicted by trials without attenua-
tion of renal microvascular complications [84,85]. This
has been mainly attributed to dose-limiting side effects
or inability to achieve adequate tissue levels of drug but
may imply that AR is not the single predominant enzyme
involved in the intricate pathways that lead to DMN but
rather contributes to the early pathogenesis in the presenceof hyperglycemia [86].
Final common pathways of diabetic microvasculardamageRegulation of vascular functions such as vasodilation, per-
meability, endothelial activation and growth factor signal-
ing occurs through intracellular signaling molecules such
as MAPK, PKC and NFB. Activation of phospholipase
C and subsequent increases in Ca2+, stimulate DAG and
leads to activation of PKC. De novo synthesisof DAG with
subsequent PKC activation can occur under metabolic
stress, leading to chronically elevated states [87]. Oxi-
dants, AGEs, hexosamine, flow abnormalitites and hy-
pertension all have been shown to alter the activities of
these kinases and upregulation of DAG, PKC, NFB and
MAPK all have been demonstrated in various diabetic an-
imal models [87] (Fig. 5).
The MAPK cascade plays a central role in a range
of biological processes relevant to DMN, including cell
Fig. 5. Final common pathway.
growth, differentiation and apoptosis. Three main groups
of MAPK (extracellularsignal regulatedkinases (ERK), c-
JunN-terminal kinases (JNK) andp38 kinases vary in their
involvement in diabetic induced nephropathy. Classicallyp38 MAP kinase is linked to osmotic stress, JNK responds
to forms of cellular stress, whereas ERKs primarily are re-
garded as growth signalingkinases.Overlap between these
different functions however has been described [87]. All
three types are thought to potentially be part of the stress
activated protein kinases (SAP). In concert all MAPKs
produce the full range of cellular adaptation found as
the basis of diabetic complications. Vascular damage due
to increased vascular permeability, alterations in blood
flow, NO dysregulation and leukocyte adhesion are the
result of increased signaling molecules, hyperosmolar
stress and dysregulation of oxidants and anti-oxidants.Associated induction of growth factors (TGF, VEGF)
and cytokines (TNF, IL1, IGF-1) is also described and
has been shown to stimulate proliferation of mesan-
gial cells, contributing to nephromegally and fibrosis
(Fig. 5).
TGF is considered to be the pivotal cytokine in me-
diating collagen formation of the kidney. Its uniquely
powerful fibrogenic potential is the result of upregula-
tion of matrix synthesis, inhibition of matrix degradation
and modulation of matrix receptor expression to facilitate
cell-matrix interactions. Induction of TGF by glucose
and glycated proteins seems to be a PKC-dependent phe-
nomenon (reviewed in 23).
Since targeting any of the single pathways by selective
inhibition causes attenuation but not complete reversion
or halt of progression in diabetic complications, it seems
that a change of expression of intracellular messengers
more downstream to all these individual pathways may
be of benefit. Development of inhibitors of intracellular
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
9/12
Diabetic NephropathyPathogenesis 245
Fig. 6. Hemodynamic and non-hemodynamic factors.
signaling molecules, however, will need to be specific
since many cellular processes are dependent on intact sig-
naling of these messengers. In search of selective isotypes
of PKC, associated with microvascular injury, 1 and
2 emerged, both of which are expressed in glomeruli
[88,89]. Specific inhibition of PKC have been shown to
prevent mesangial expansion and glomerular dysfunction
in diabetic mice [90,91].
Interaction between hemodynamic
and metabolic factors
Interaction of hemodynamic factors such as increased
systemic and intraglomerular pressures, activation of the
RAAS with subsequent hemodymanic changes, increase
in endothelin/EDRF and other vaso-active hormones with
metabolic changes including ROS, AGE, polyols, an-
giotensin, reduction of nephrin, cell growth stimulants
and increase in cellular matrix, cytokine and intracellu-
lar mediators compound the deleterious effects of the dia-
betic milieu (Fig. 6). This constellation of factors reduces
the threshold for injury via a final common pathway of
increases in intracellular messengers (PKC, MAPK), nu-
clear transcription factors (NFB) and growth factors (cy-
tokine, TGFand VEGF). All these changes subsequently
result in development of proteinuria, glomerulosclerosisand tubulo-interstitial fibrosis. It is of note that the inter-
action of hemodynamic and nonhemodynamic pathways
seems to involve TGF, making it a prime candidate for
development of antagonists to treat diabetic nephropathy.
References
1. USRDS Reportincidence and prevalence of ESRD.Am J Kidney
Dis2003;41(452): 4256.
2. Fenton SS, Schaubel DE, Desmeules M, Morrison HI, Mao Y,
Copleston P, Jeffery JR, Kjellstrand CM. Hemodialysis versus peri-
toneal dialysis: A comparison of adjusted mortality rates. Am J Kid-
ney Dis1997;30:334342.
3. Chantrel F, Enache I, Bouiller M, Kolb I, Kunz K, Petitjean P,
MoulinB, Hannedouche T. Abysmal prognosis of patients with type
2 diabetes entering dialysis.Nephrol Dial Transplant1999;14:129
136.
4. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mel-
litus.N Engl J Med1999;341:11271133.
5. Bowden DW, Sale M, Howard TD, Qadri A, Spray BJ, Rothschild
CB, Akots G, Rich SS, Freedman BI. Linkage of genetic markers
on human chromosomes 20 and 12 to NIDDM in Caucasian sib
pairs with a history of diabetic nephropathy.Diabetes 1997;46:882
886.
6. Krolewski AS. Genetics of diabetic nephropathy: Evidence for ma-
jor and minor gene effects.Kidney Int1999;55:15821596.
7. Deckert T, Horowitz IM, Kofoed-Enevoldsen A, Kjellen L, Deckert
M, Lykkelund C, Burcharth F. Possible genetic defects in regula-tion of glycosaminoglycans in patients with diabetic nephropathy.
Diabetes1991;40:764770.
8. Bank N. Mechanisms of diabetic hyperfiltration. Kidney Int
1991;40:792807.
9. Bank N, Aynedjian HS. Progressive increases in luminal glucose
stimulate proximal sodium absorption in normal and diabetic rats.
J Clin Invest1990;86:309316.
10. Kreisberg JI. Insulin requirement for contraction of cultured rat
glomerular mesangial cells in response to angiotensin II: Possible
role for insulin in modulating glomerular hemodynamics. Proc Natl
Acad Sci USA1982;79:41904192.
11. Kamm KE, Stull JT. Regulation of smooth muscle contractile ele-
ments by second messengers. Annu Rev Physiol1989;51:299313.
12. Bank N, Lahorra MA, Aynedjian HS. Acute effect of calcium
and insulin on hyperfiltration of early diabetes. Am J Physiol
1987;252:E13E20.
13. Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V.
Ornithine decarboxylase, kidney size, and the tubular hypothesis of
glomerular hyperfiltration in experimental diabetes. J Clin Invest
2001;107:217224.
14. Wakabayashi I, Hatake K, Kimura N, Kakishita E, Nagai K. Modu-
lationof vascular tonusby the endotheliumin experimental diabetes.
Life Sci 1987;40:643648.
15. Veelken R, Hilgers KF, Hartner A, Haas A, Bohmer KP, Sterzel
RB. Nitric oxide synthase isoforms and glomerular hyperfiltration
in early diabetic nephropathy. J Am Soc Nephrol 2000;11:7179.
16. Choi KC, Kim NH, An MR, Kang DG, Kim SW, Lee J. Alter-
ations of intrarenal renin-angiotensin and nitric oxide systems in
streptozotocin-induced diabetic rats.Kidney Int Suppl 1997;60:S23
S27.
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
10/12
246 van Dijk and Berl
17. Ichihara A, Inscho EW, Imig JD, Navar LG. Neuronal nitric oxide
synthase modulates rat renal microvascular function. Am J Physiol
1998;274:F516F524.
18. Komers R, Anderson S. Paradoxes of nitric oxide in the diabetickidney. Am J Physiol Renal Physiol2003;284:F1121F1137.
19. Baumgartl HJ, Sigl G, Banholzer P, Haslbeck M, Standl E. On the
prognosis of IDDMpatients withlarge kidneys.Nephrol Dial Trans-
plant1998;13:630634.
20. Wiseman MJ, Saunders AJ, Keen H, Viberti G. Effect of blood
glucose control on increased glomerular filtration rate and kidney
size in insulin-dependent diabetes. N Engl J Med 1985;312:617
621.
21. Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, De-
Fronzo RA. Effect of strict glycemic control on renal hemodynamic
response to amino acids and renal enlargement in insulin-dependent
diabetes mellitus.N Engl J Med1991;324:16261632.
22. Flyvbjerg A. Putative pathophysiological role of growth factors and
cytokines in experimental diabetic kidney disease. Diabetologia
2000;43:12051223.23. Cooper ME. Interaction of metabolic and haemodynamic fac-
tors in mediating experimental diabetic nephropathy. Diabetologia
2001;44:19571972.
24. Taft JL, Nolan CJ, Yeung SP, Hewitson TD, Martin FI. Clinical
and histological correlations of decline in renal function in diabetic
patients with proteinuria.Diabetes1994;43:10461051.
25. Gandhi M, Olson JL, Meyer TW. Contribution of tubular injury to
loss of remnant kidney function.Kidney Int1998;54:11571165.
26. Fioretto P, Mauer M, Brocco E, Velussi M, Frigato F, Muollo B,
Sambataro M, Abaterusso C, Baggio B, Crepaldi G, Nosadini R.
Patterns of renal injury in NIDDM patients with microalbuminuria.
Diabetologia1996;39:15691576.
27. Nuyts GD, Yaqoob M, Nouwen EJ, Patrick AW, McClelland P,
MacFarlane IA, Bell GM, DeBroe ME. Human urinary intestinal
alkaline phosphatase as an indicator of S3-segement-specific alter-ations in incipient diabetic nephropathy. Nephrol Dial Transplant
1994;9:377381.
28. Gilbert RE, Cooper ME. The tubulointerstitium in progressive dia-
betic kidney disease: More than an aftermath of glomerular injury?
Kidney Int1999;56:16271637.
29. CaoZ, Cooper ME.Role of angiotensin II in tubulointerstitial injury.
Semin Nephrol2001;21:554562.
30. Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR.
The changing natural history of nephropathy in type I diabetes. Am
J Med1985;78:785794.
31. Mogensen CE. Microalbuminuria as a predictor of clinical diabetic
nephropathy.Kidney Int1987;31:673689.
32. AdlerAI, Stevens RJ,Manley SE,Bilous RW, CullCA, HolmanRR.
Development and progressionof nephropathyin type2 diabetes:The
United Kingdom Prospective Diabetes Study (UKPDS 64). KidneyInt2003;63:225232.
33. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH,
Krolewski AS. Regression of microalbuminuria in type 1 diabetes.
N Engl J Med2003;348:22852293.
34. Gambaro G, Cavazzana AO, Luzi P, Piccoli A, Borsatti A, Crepaldi
G, Marchi E, Venturini AP, Baggio B. Glycosaminoglycans prevent
morphological renal alterations and albuminuria in diabetic rats.
Kidney Int1992;42:285291.
35. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The ef-
fect of dietary protein restriction on the progression of diabetic
and nondiabetic renal diseases: A meta-analysis.Ann Intern Med
1996;124:627632.
36. Kalk WJ, Osler C, Constable J, Kruger M, Panz V. Influence of di-
etary protein on glomerular filtration and urinary albumin excretion
in insulin-dependent diabetes.Am J Clin Nutr1992;56:169173.
37. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syn-
drome among US adults: Findings from the third National Health
and Nutrition Examination Survey.JAMA2002;287:356359.
38. Bakris G, Williams M, Dworkin L, Elliott W, Epstein M, Toto R,Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function
in adultswith hypertension anddiabetes:A consensus approach.Am
J Kidney 2000;36:646661.
39. Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ. Effect of intensive
blood pressure control on the course of type 1 diabetic nephropathy.
Collaborative Study Group.Am J Kidney Dis1999;34:809817.
40. ChobanianAV, BakrisGL, BlackHR, CushmanWC,GreenLA,Izzo
JL, Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ.
The seventh report of the joint national committee on prevention,
detection,evaluation, and treatment of highblood pressure:The JNC
7 report.Jama2003;289:25602572.
41. TaalMW, Chertow GM,Rennke HG,Gurnani A,JiangT,Shahsafaei
A, Troy JL, Brenner BM, Mackenzie HS. Mechanisms underly-
ing renoprotection during renin-angiotensin system blockade.Am J
Physiol Renal Physiol2001;280:F343F355.42. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis
JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect
of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med2001;345:851
860.
43. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE,
Parving HH,RemuzziG, Snapinn SM,ZhangZ, ShahinfarS. Effects
of losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J Med2001;345:861869.
44. Cao Z, Kelly DJ, Cox A, Casley D, Forbes JM, Martinello P, Dean
R, GilbertRE, Cooper ME.Angiotensin type 2 receptor is expressed
in the adult rat kidney and promotes cellular proliferation and apop-
tosis.Kidney Int2000;58:24372451.
45. Taal MW, Nenov VD, Wong W, Satyal SR, Sakharova O, Choi JH,
Troy JL, BrennerBM. Vasopeptidase inhibition affords greater reno-protection than angiotensin-converting enzyme inhibition alone. J
Am Soc Nephrol2001;12:20512059.
46. Heidland A, SebekovaK, Schinzel R. Advanced glycationend prod-
ucts and the progressive course of renal disease. Am J Kidney Dis
2001;38:S100S106.
47. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end
products in tissue and the biochemical basis of diabetic complica-
tions.N Engl J Med1988;318:13151321.
48. Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney
V, Friedman EA, Cerami A, Vlassara H. Advanced glycosylation
end products in patients with diabetic nephropathy. N Engl J Med
1991;325:836842.
49. TanjiN, MarkowitzGS, Fu C, Kislinger T, TaguchiA, Pischetsrieder
M, Stern D, Schmidt AM, DAgati VD. Expression of advanced
glycation end products and their cellular receptor RAGE in dia-betic nephropathy and nondiabetic renal disease. J Am Soc Nephrol
2000;11:16561666.
50. Charonis AS, Tsilbary EC. Structural and functional changes of
laminin and typeIV collagen afternonenzymatic glycation.Diabetes
1992;41(Suppl 2):4951.
51. Forbes J,Thallas T, ThomasMC, FoundsHW, Burns WC,Jerums G,
Cooper ME. The breakdown of preexisting advanced glycation end
products is associated with reduced renal fibrosis in experimental
diabetes. 2003FASEB J2003;17:17621764.
52. Wautier MP, Chappey O, Corda S, Stern DM,Schmidt AM,Wautier
JL. Activation of NADPH oxidase by AGE links oxidant stress to
altered gene expression via RAGE.Am J Physiol Endocrinol Metab
2001;280:E685E694.
53. Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert
A,ThallasV, AtkinsRC, OsickaT,Jerums G,CooperME. Advanced
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
11/12
Diabetic NephropathyPathogenesis 247
glycation end products causeepithelial-myofibroblast transdifferen-
tiation via thereceptor for advanced glycation end products (RAGE).
J Clin Invest2001;108:18531863.
54. Lal MA, Brismar H, Eklof AC, Aperia A. Role of oxidative stress inadvanced glycation end product-induced mesangial cell activation.
Kidney Int2002;61:20062014.
55. Li J, Schmidt AM. Characterization and functional analysis of the
promoter of RAGE, the receptor for advanced glycation end prod-
ucts.J Biol Chem 1997;272:1649816506.
56. Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky
D, Nowygrod R, Neeper M, Przysiecki C, Shaw A. Survey of
the distribution of a newly characterized receptor for advanced
glycation end products in tissues. Am J Pathol 1993;143:1699
1712.
57. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-
products: A review.Diabetologia2001;44:129146.
58. Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, Maeda K,
KurokawaK, van Ypersele de Strihou C. Implication of an increased
oxidative stressin the formationof advanced glycation endproductsin patients with end-stage renal failure. Kidney Int1997;51:1170
1181.
59. Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC,
Brammar GC, Lee F, Grant SL, Burrell LA, Jerums G, Osicka TM.
Reduction of the accumulation of advanced glycation end products
by ACE inhibition in experimental diabetic nephropathy. Diabetes
2002;51:32743282.
60. Yang CW, Vlassara H, Peten EP, He CJ, Striker GE, Striker LJ. Ad-
vancedglycation end products up-regulate gene expression found in
diabetic glomerular disease. ProcNatl Acad SciUSA 1994;91:9436
9440.
61. Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M.
Advanced glycation end products induce glomerular sclerosis and
albuminuriain normalrats. ProcNatl Acad SciUSA 1994;91:11704
11708.62. Reactive Oxygen Species and Diabetic Nephropathy. Proceedings
of the Hyonam Kidney Laboratory, Soon Chun Hyang University
International Diabetes Symposium. Seoul, Korea, January 1819,
2003.J Am Soc Nephrol2003;14:S209S296.
63. Kuroki T, Isshiki K, King GL. Oxidative stress: The lead or support-
ing actor in the pathogenesis of diabetic complications.J Am Soc
Nephrol2003;14:S216S220.
64. BaynesJW.Role of oxidativestressin development of complications
in diabetes.Diabetes1991;40:405412.
65. SuzukiS, Hinokio Y, Komatu K,OhtomoM, OnodaM, HiraiS, Hirai
M,HiraiA, ChibaM, KasugaS, Akai H,ToyotaT.Oxidativedamage
to mitochondrial DNAand its relationship to diabetic complications.
Diabetes Res Clin Pract1999;45:161168.
66. Rhee SG, Chang TS, Bae YS, Lee SR, Kang SW. Cellular reg-
ulation by hydrogen peroxide. J Am Soc Nephrol 2003;14:S211S215.
67. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase:
Role in cardiovascular biology and disease. Circ Res2000;86:494
501.
68. ShioseA, KurodaJ, TsuruyaK, HiraiM, HirakataH, NaitoS, Hattori
M, Sakaki Y, Sumimoto H. A novelsuperoxide-producingNAD(P)H
oxidase in kidney.J Biol Chem 2001;276:14171423.
69. Guzik TJ, West NE, Black E, McDonald D, Ratnatunga C, Pillai
R, Channon KM. Vascular superoxide production by NAD(P)H ox-
idase: Association with endothelial dysfunction and clinical risk
factors.Circ Res 2000;86:E85E90.
70. Devaraj S, Hirany SV, Burk RF, Jialal I. Divergence between LDL
oxidative susceptibility and urinary F(2)-isoprostanes as measures
of oxidative stress in type 2 diabetes. Clin Chem 2001;47:1974
1979.
71. Lerman LO, Nath KA, Rodriguez-Porcel M, Krier JD, Schwartz
RS, Napoli C, Romero JC. Increased oxidative stress in exper-
imental renovascular hypertension. Hypertension 2001;37:541
546.72. Greene DA, Lattimer SA, Sima AA. Sorbitol, phospho-
inositides, and sodium-potassium-ATPase in the pathogene-
sis of diabetic complications. N Engl J M ed 1987;316:599
606.
73. Mauer SM, Steffes MW, Azar S, Brown DM. Effects of sorbinil on
glomerular structure and function in long-term-diabetic rats. Dia-
betes1989;38:839846.
74. Yue DK, Hanwell MA, Satchell PM, Turtle JR. The effect of aldose
reductase inhibition on motor nerve conduction velocity in diabetic
rats.Diabetes1982;31:789794.
75. Robison WG, Jr, Nagata M, Laver N, Hohman TC, Kinoshita
JH. Diabetic-like retinopathy in rats prevented with an aldose
reductase inhibitor. Invest Ophthalmol Vis Sci 1989;30:2285
2292.
76. Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyolpathway to diabetes-induced oxidative stress. J Am Soc Nephrol
2003;14:S233S236.
77. Steer KA, Sochor M, McLean P. Renal hypertrophy in experimental
diabetes. Changes in pentose phosphate pathway activity.Diabetes
1985;34:485490.
78. Lee AY, Chung SK, Chung SS. Demonstration that polyol accumu-
lation is responsible for diabetic cataract by the use of transgenic
mice expressing the aldose reductase gene in the lens. Proc Natl
Acad Sci USA1995;92:27802784.
79. Terubayashi H, Sato S, Nishimura C, Kador PF, Kinoshita JH. Lo-
calization of aldose and aldehyde reductase in the kidney. Kidney
Int1989;36:843851.
80. Ghahary A, Luo JM, Gong YW, Chakrabarti S, Sima AA, Murphy
LJ. Increased renal aldose reductase activity, immunoreactiv-
ity, and mRNA in streptozocin-induced diabetic rats. Diabetes1989;38:10671071.
81. KanekoM, Carper D, Nishimura C, Millen J,Bock M,Hohman TC.
Induction of aldose reductase expression in rat kidney mesangial
cells and Chinese hamster ovary cells under hypertonic conditions.
Exp Cell Res1990;188:135140.
82. Heesom AE, Hibberd ML, Millward A, Demaine AG. Polymor-
phism in the 5-end of the aldose reductase gene is strongly associ-
ated with thedevelopment of diabeticnephropathy in type I diabetes.
Diabetes1997;46:287291.
83. Shah VO, Dorin RI, Sun Y, Braun M, Zager PG. Aldose reduc-
tase gene expression is increased in diabetic nephropathy. J Clin
Endocrinol Metab 1997;82:22942298.
84. Ranganathan S, Krempf M, Feraille E, Charbonnel B. Short term
effect of an aldose reductase inhibitor on urinary albumin excretion
rate (UAER) and glomerular filtration rate (GFR) in type 1 diabeticpatients with incipient nephropathy. Diabete Metab 1993;19:257
261.
85. McAuliffe AV, Brooks BA, Fisher EJ, Molyneaux LM, Yue DK.
Administration of ascorbic acid and an aldose reductase inhibitor
(tolrestat) in diabetes: Effect on urinary albumin excretion.Nephron
1998;80:277284.
86. Sheetz MJ, King GL. Molecular understanding of hyperglycemias
adverse effects for diabetic complications. JAMA 2002;288:2579
2588.
87. Tomlinson DR. Mitogen-activated protein kinases as glucose trans-
ducers for diabetic complications. Dianetologia 1999;42:1271
1281.
88. Ishii H, Koya D, King GL. Protein kinase C activation and its role
in the development of vascular complications in diabetes mellitus.
J Mol Med1998;76:2131.
-
8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy
12/12
248 van Dijk and Berl
89. Meier M, King GL. Protein kinase C activation and its pharmaco-
logical inhibition in vascular disease.Vasc Med2000;5:173185.
90. Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell
SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, KingGL. Amelioration of vascular dysfunctions in diabetic rats by an
oral PKC beta inhibitor. Science1996;272:728731.
91. Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda
S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL,
Kikkawa R. Amelioration of accelerated diabetic mesangial ex-
pansion by treatment with a PKC beta inhibitor in diabetic db/dbmice, a rodent model for type 2 diabetes. Faseb J 2000;14:439
447.