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Aims/Introduction: The polyol pathway has long been involved in the pathogenesis of diabetic nephropathy. It remains still unclear, however, how the polyol pathway is implicated in this process. We explored the effects of the enhanced polyol pathway on renocortical tubular cells and glomeruli in experimentally‐induced diabetes.

The present study was designed to examine the effect of aldose reductase (AR) overexpression on the development of diabetic neuropathy by using mice transgenic for human AR. At 8 weeks of age, transgenic mice (Tg) and non-transgenic littermates (Lm) were made diabetic with streptozotocin. After 8 weeks of untreated diabetes, plasma glucose levels and the reduction in body weight were similar between the groups of diabetic animals. Despite the comparable levels of hyperglycaemia, levels of sorbitol and fructose were significantly greater in the peripheral nerve of diabetic Tg than in diabetic Lm (both P < 0.01). Ouabain sensitive Na+,K+-ATPase activity was similarly decreased in both diabetic Tg and Lm. Protein kinase C activity in the sciatic nerve membrane fraction was unaffected by diabetes in Lm, but was reduced by nearly 40% in the diabetic Tg. Although both groups of diabetic animals exhibited a significant decrease in tibial nerve motor nerve conduction velocity (MNCV), this decrease was significantly more severe (P < 0.01) in diabetic Tg than in diabetic Lm. Consistent with these findings, nerve fibre atrophy was significantly more severe in diabetic Tg than in diabetic Lm (P < 0.01). These findings implicate increased polyol pathway activity in the pathogenesis of diabetic neuropathy. In support of this hypothesis, treating diabetic Tg with an aldose reductase inhibitor (WAY121-509, 4 mg/kg/day) for 8 weeks significantly prevented the accumulation of sorbitol, the decrease in MNCV and the increased myelinated fibre atrophy in diabetic Tg.

To explore the relationships between polyol pathway-related enzymes and pathologic features, we examined the immunohistochemical expression of aldose reductase (AR) and sorbitol dehydrogenase (SDH) in the peripheral nerve and kidney tissues collected postmortem from diabetic patients and compared it with those from non-diabetic patients. Tissue AR protein concentrations were also quantified. In non-diabetic patients, AR distributed in pericytes, smooth muscle cells of endo- and epi-neurial microvessels, Schwann cells in the sciatic nerve, and tubular cells of the renal medulla. By contrast, positive SDH reactions were observed in tubular cells of the renal cortex but were faint in the sciatic nerve. Diabetic patients frequently showed dense AR expressions in the sciatic nerve. In nephropathic diabetic patients, the glomerular mesangial area showed diffuse positive reactions for AR. The severity of structural changes in glomeruli correlated with the intensity of immunoreactive AR (r2=0.626,P<0.01). AR contents in the renal cortex and sciatic nerve from diabetic patients were 1.5- and 1.8-fold greater than those from non-diabetic patients, respectively (P<0.05 for both). These findings are the first to demonstrate enhanced AR expressions in peripheral nerve and renal glomeruli in diabetic patients and its relevance to the characteristic pathology.