Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in Type 2 diabetic patients

Iso, Kaoru; Tada, Hayato; Kuboki, Koji; Inokuchi, Toshiki

doi:10.1016/s1056-8727(01)00160-x

Cited by 61 publications

(34 citation statements)

References 14 publications

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“…In regard to the magnitude of induction of cytoplasmic antioxidant enzymes, it should be noted that a difference of two-fold in the renal expression level of CuZnSOD in transgenic mice has been shown to ameliorate experimental diabetic nephropathy (39). Therefore the magnitude of the changes described herein may be quite relevant to the progression rate of human diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 83%

The Response of Antioxidant Genes to Hyperglycemia Is Abnormal in Patients With Type 1 Diabetes and Diabetic Nephropathy

et al. 2003

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Increased flux of glucose through the polyol pathway may cause generation of excess reactive oxygen species (ROS), leading to tissue damage. Abnormalities in expression of enzymes that protect against oxidant damage may accentuate the oxidative injury. The expression of catalase (CAT), CuZn superoxide-dismutase (CuZn-SOD), glutathione peroxidase (GPX), and Mn superoxide-dismutase (MnSOD) mRNA was quantified in peripheral blood mononuclear cells-obtained from 26 patients with type 1 diabetes and nephropathy, 15 with no microvascular complications after 20 years' duration of diabetes, and 10 normal healthy control subjectsthat were exposed in vitro to hyperglycemia (HG) (31 mmol/l D-glucose). Under HG, there was a twofold increase in the expression of CAT, CuZnSOD, and GPX mRNA in the patients without complications and the control subjects versus patients with nephropathy (P < 0.0001), and MnSOD did not change in any of the groups. The aldose reductase inhibitor zopolrestat partially restored the levels of CAT, CuZnSOD, and GPX mRNA in the patients with nephropathy (P < 0.05). There was a highly significant correlation between increased aldose reductase (ALR2) expression, CAT, CuZnSOD, and GPX mRNA levels under HG conditions and polymorphisms of ALR2 in the patients with nephropathy (P < 0.00001). In conclusion, these results suggest that high glucose flux through aldose reductase inhibits the expression of antioxidant enzymes.

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Section: Discussionmentioning

confidence: 83%

The Response of Antioxidant Genes to Hyperglycemia Is Abnormal in Patients With Type 1 Diabetes and Diabetic Nephropathy

et al. 2003

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“…Several ALR2 inhibitors have been used with limited success in patients with diabetic nephropathy (20). In this light, despite optimization of therapies, type 2 diabetic patients with nephropathy have substantial residual risk of ESRD.…”

Section: Sample Size Estimationmentioning

confidence: 99%

“…In the Asian subgroup analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study, 10% of type 2 diabetic patients with nephropathy continued to develop ESRD on a yearly basis despite optimal risk factor control and inhibition of the renin-angiotensin system (21). Given the antiproteinuric effects of ALR2 inhibitors (20) and the fact that reduction in proteinuria predicts future risk of cardiorenal end points (21), our findings raise the possibility of using pathway-specific treatment to further reduce risk of complications.…”

Section: Sample Size Estimationmentioning

confidence: 99%

Aldose Reductase Genotypes and Cardiorenal Complications

Wang

et al. 2008

Diabetes Care

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OBJECTIVE -We report the independent risk association of type 2 diabetic nephropathy with the zϪ2 allele of the 5Ј-(CA) n microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design.RESEARCH DESIGN AND METHODS -In this 8-year prospective cohort of 1,074 type 2 diabetic patients (59% male, median age 61 years; disease duration 7 years) with an observation period of 8,592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease at recruitment. The renal end point was defined as new onset of estimated glomerular filtration rate Ͻ60 ml/min per 1.72 m 2 or hospitalizations with dialysis or death due to renal disease, and CHD was defined as hospitalizations with myocardial infarction, ischemic heart disease, or related deaths.RESULTS -After controlling for baseline risk factors and use of medications, we found that the ALR2 zϪ2 allele of (CA) n microsatellite carriers had increased risk of renal (hazard ratio 1.53 [95% CI 1.14 -2.05], P ϭ 0.005) or combined cardiorenal (1.31 [1.01-1.72], P ϭ 0.047) end points. Carriers of the ALR2 C-106T polymorphism also had increased risk of renal (1.54 [1.15-2.07], P ϭ 0.004) and cardiorenal (1.49 [1.14 -1.95], P ϭ 0.004) end points. Compared with noncarriers, patients with two risk-conferring genotypes had a twofold increased risk of renal (2.41 [1.57-3.70], P Ͻ 0.001) and cardiorenal (1.94 [1.29 -2.91], P ϭ 0.002) end points.CONCLUSIONS -In Chinese type 2 diabetic patients, genetic polymorphisms of ALR2 independently predicted new onset of renal and cardiorenal end points, with the latter being largely mediated through renal disease.

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“…At the end of the study conducted for 5 years, urinary albumin excretion increased significantly in the control group whereas it remained unchanged in the epalrestat-treated group. However, the reduction rate of reciprocal creatinine in the epalrestat-treated group was significantly smaller than that in the control group [114].…”

Section: Nephropathymentioning

confidence: 65%

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

Zhu¹

2013

Diabetes Mellitus - Insights and Perspectives

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Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in Type 2 diabetic patients

Cited by 61 publications

References 14 publications

The Response of Antioxidant Genes to Hyperglycemia Is Abnormal in Patients With Type 1 Diabetes and Diabetic Nephropathy

The Response of Antioxidant Genes to Hyperglycemia Is Abnormal in Patients With Type 1 Diabetes and Diabetic Nephropathy

Aldose Reductase Genotypes and Cardiorenal Complications

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

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