Polymorphism in the 5'-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes

Heesom, A. E.; Hibberd, M. L.; Millward, Ann; Demaine, Andrew G.

doi:10.2337/diabetes.46.2.287

Cited by 81 publications

(92 citation statements)

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“…To test the previously reported association [4], we genotyped the 5 ¢-ALR2 polymorphism in the promoter of the aldose reductase gene [3,4] in all 474 patients. Genotyping for the 5 ¢-ALR2 marker was done by polymerase chain reaction (PCR)-based protocols using the previously reported primer sequences [3].…”

Section: Methodsmentioning

confidence: 99%

The role of aldose reductase gene in the susceptibility to diabetic nephropathy in Type II (non-insulin-dependent) diabetes mellitus (Short Communication)

et al. 1999

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Section: Methodsmentioning

confidence: 99%

The role of aldose reductase gene in the susceptibility to diabetic nephropathy in Type II (non-insulin-dependent) diabetes mellitus (Short Communication)

et al. 1999

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“…However, this contradicts numerous reports of (1) alleviation, rather than aggravation, of oxidative-nitrosative stress by AR inhibitors in other tissues of diabetic animals as discussed above, and (2) beneficial effects of both AR inhibitors and antioxidants on experimental DN [4,5,14,15]. Furthermore, several groups demonstrated that prevalence of DN depends on (1) erythrocyte AR content, and/or (2) frequency of the z-2 allele of the AR gene, in human subjects with diabetes mellitus [4,67,68]. Homozygosity for the z-2 allele in Type 1 (insulin-dependent) diabetes is associated with an increased expression of the AR gene and DN [67].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several groups demonstrated that prevalence of DN depends on (1) erythrocyte AR content, and/or (2) frequency of the z-2 allele of the AR gene, in human subjects with diabetes mellitus [4,67,68]. Homozygosity for the z-2 allele in Type 1 (insulin-dependent) diabetes is associated with an increased expression of the AR gene and DN [67]. In Type 2 (non-insulin-dependent diabetes), the z-2 allele is also associated with an increased AR activity and nephro-retinopathy [68].…”

Section: Discussionmentioning

confidence: 99%

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Drel

Pacher²,

Stevens

et al. 2006

Free Radical Biology and Medicine

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Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADPribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg −1 day −1 ) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetesinduced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM Lglucose or 30 mM D-glucose plus 10 μM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.

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“…In the rat model, decreased renal NO accelerates the progression of DN, presumably through mechanisms such as increased renal vascular tone and potentiation of angiotensin II effects. 42 Interestingly, the eNOS gene is located on chromosome 7q35 43 and the gene coding for aldose reductase 44 ; a candidate gene for genetic susceptibility to DN in type 1 diabetic patients 45 has been located on the same chromosomal region. Therefore, it may be a candidate region for genetic susceptibility to diabetic microvascular complications.…”

Section: Discussionmentioning

confidence: 99%

Impact of Nitric Oxide Synthase Glu298Asp Polymorphism on the Development of End-Stage Renal Disease in Type 2 Diabetic Egyptian Patients

Bessa

Hamdy

2011

Renal Failure

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Background: Nitric oxide is an important regulator of renal hemodynamics. This study aimed to investigate the role of endothelial nitric oxide synthase (eNOS) gene polymorphism in type 2 diabetic patients with end-stage renal disease (ESRD) and to elucidate any alteration of nitric oxide synthase (NOS) activity caused by this polymorphism. Methods: The study included 80 patients with type 2 diabetes of >10 years duration (40 with diabetes-derived ESRD, 40 without nephropathy) and 20 healthy controls. Plasma nitrate/nitrite level, and serum NOS activity were measured and eNOS Glu298Asp genotypes were determined. Results: The frequency of Glu/Glu (GG) genotype in diabetics with ESRD was lower than controls. However, the frequency of Asp/Asp (TT) genotype was increased in diabetics with ESRD as compared to those without nephropathy and controls. Diabetics with ESRD had significantly lower nitrate/nitrite level and NOS activity than those without nephropathy. Diabetic patients with TT genotype are at a significant risk for ESRD. Moreover, subjects carrying TT genotype had lower nitrate/nitrite level and NOS activity than those carrying GG genotype. In diabetics with ESRD, creatinine clearance was positively correlated with both nitrate/nitrite level and NOS activity. Conclusions: These results imply that TT genotype of eNOS may be associated with an increased risk of ESRD in Egyptian type 2 diabetics. It could represent a useful genetic marker to identify diabetics at high risk for the development of ESRD. However, larger future prospective studies are required to confirm the role of eNOS gene polymorphism in the progression of diabetic nephropathy to ESRD.

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Polymorphism in the 5'-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes

Cited by 81 publications

References 0 publications

The role of aldose reductase gene in the susceptibility to diabetic nephropathy in Type II (non-insulin-dependent) diabetes mellitus (Short Communication)

The role of aldose reductase gene in the susceptibility to diabetic nephropathy in Type II (non-insulin-dependent) diabetes mellitus (Short Communication)

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Impact of Nitric Oxide Synthase Glu298Asp Polymorphism on the Development of End-Stage Renal Disease in Type 2 Diabetic Egyptian Patients

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