Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.BackgroundDespite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of d-glucose.MethodsPBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11mmol/L d-glucose) or supplemented with 10mmol/L d-glucose (moderate hyperglyemia) or 20mmol/L d-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay.ResultsALR2 mRNA levels were significantly elevated with increasing d-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z–2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007).ConclusionThese results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.