Z−2 Microsatellite Allele Is Linked to Increased Expression of the Aldose Reductase Gene in Diabetic Nephropathy1

Abstract

Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A-C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells. At UNMHSC we identified 10 alleles ranging from Z-10 to Z+8. The prevalence of the Z-2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z-2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z-2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z-2, and 69% and 32%, respectively, had 1 copy or more of Z-2. Among diabetics, homozygosity for the Z-2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71-17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 +/- 0.050) than in group I (0.068 +/- 0.025), group II (0.042 +/- 0.020), or group IV (0.015 +/- 0.011; P < 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z-2 homozygotes (0.098 +/- 0.06) and Z-2 heterozygotes (0.080 +/- 0.04) than in patients with no Z-2 allele (0.043 +/- 0.02; P < 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z-2 homozygotes (0.034 +/- 0.04) and Z-2 heterozygotes (0.038 +/- 0.03) were similar to levels in patients without a Z-2 allele (0.047 +/- 0.03; P = NS). At HSR we identified eight alleles ranging from Z- 12 to Z+2. The prevalence of the Z-2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z-2, and 81% had one copy or more of the Z-2 allele. In contrast, in group II, 4% were homozygous for Z-2, and 36% had one copy or more of the Z-2 allele. IDDM patients homozygous for Z-2 had an increased risk for DN compared with those lacking the Z-2 allele (OR, 18; 95% confidence interval, 2-159). IDDM patients who had one copy or more of Z-2 had increased risk (OR, 7.5; 95% confidence interval, 1.9-29.4) for DN compared with those without the Z-2 allele. These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z 2 al...

Glucomannans Alleviated the Progression of Diabetic Kidney Disease by Improving Kidney Metabolic Disturbance

“…In the present study, the highest level of hexosamines was observed in the model group. On the other hand, long‐term hyperglycemia would activate the aldose reductase (AR), resulting in the accumulation of sorbitol, insufficiency of NADPH and intracellular inositol and enhanced oxidative stress in kidney cells . In the present study, activated polyol metabolic pathway was observed in the model group, which accompanied with a higher concentration of pentoses, lower levels of inositol (Figure H), and glucomannan treatment improved the metabolic pathway by modification of alcohols and inositol profile.…”

Molecular Genetic Approaches for Studying the Etiology of Diabetic Nephropathy

“…An (AC)n microsatellite polymorphism, located 2.1 kb upstream of AKR1B1, was initially reported to be associated with early onset retinopathy in Chinese type 2 diabetic patients [80]. Subsequent studies investigating whether this marker is associated with DN have yielded mixed results [79,[81][82][83][84][85][86][87][88]. NeatmatAllah et al undertook a small meta-analysis of the ( A C ) n marker and found no evidence for an association between the putative Z-2 allele and DN in five studies on type 2 diabetic patients [87].…”

Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

“…Recently these studies have been extended to include expression of the ALR2 gene. Patients with T1DM and nephropathy have been found to have three fold higher ALR2 mRNA levels compared to those without nephropathy or non-diabetic renal disease and using highly sensitive ribonuclease protection assays (RPA) this increase was found to be closely linked with the Z-2 5'ALR2 allele [103,104]. Patients with at least one copy of the Z-2 allele had more than two fold higher levels of ALR2 mRNA compared to those without.…”