paper - pathogenesis of diabetic nephropathy

8/13/2019 Paper - Pathogenesis of Diabetic Nephropathy

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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


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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.


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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


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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.


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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


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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.


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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


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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


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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.


10/12


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


11/12


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.


12/12


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.

paper - pathogenesis of diabetic nephropathy

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