Aldose Reductase And Diabetic Nephropathy
Aldose reductase is a key enzyme of the polyol pathway, involved in the metabolism of glucose and the NADPH-dependent reduction of a broad range of carbonyl compounds. In particular, the downstream accumulation of sorbitol and activation of the hexose kinase pathway have been implicated in the pathogenesis of a number of diabetic complications, including nephropathy.86,87 Recent studies have shown that polymorphisms in the aldose reductase gene may be associated with susceptibility to nephropathy in patients with both type 188 and type 2 diabetes.89 In particular, the polymorphism in the (A-C)n microsatellite repeat sequence (located upstream of the transcription start site) may modulate expression of the aldose reductase gene. Among the eight different alleles at this site, the Z-2 allele is associated with upregulated expression of the aldose reductase gene in the presence of hyperglycaemia90 and increased prevalence of the nephropathy.91 Segregation of the Z-2 allele has also been demonstrated from diabetic parent to affected sibling with nephropathy.92 However, individuals with the Z+2 allele are more than seven times less likely to develop diabetic renal disease than those without this marker (although this may reflect the absence of the Z-2 allele rather than a specific protective trait). Again, not all studies support this association.89,93,94 In a recent large study, Fanelli et al95 failed to demonstrate that microsatellite polymorphisms contributed significantly to nephropathy in the combined GENEDIAB and SURGENE populations. Moreover, it is not clear that the putative risk associated with these polymorphisms is related to aldose reductase. Recent work suggests that the gene coding for endothelial nitric oxide synthase may be localized to the same chromosomal region as aldose reductase.96 In addition, other polymorphisms in the aldose reductase gene (specifically the 106 polymorphism) may better correlate with the development of nephropathy than the microsatellite polymorphisms.89
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