We investigated the role of the aldose reductase pathway in the pathogenesis of the nephropathy of rats with severe (non-insulin-treated) streptozocin-induced diabetes of 6 mo duration. The initial experiment included four groups of rats: diabetic and control animals on a 20% protein diet, which were untreated or treated with sorbinil (an aldose reductase inhibitor). Food intake was increased by diabetes but was uninfluenced by sorbinil, whereas urinary urea nitrogen excretion was increased and body weight was decreased by both variables. Glomerular basement membrane (GBM) width was increased by diabetes and decreased by sorbinil. No other structural changes were noted. We speculate that sorbinil could have slowed the abnormal rate of GBM thickening in diabetic rats and the normal increase in GBM width in control rats by inducing a mild catabolic state. The second experiment also involved four groups of rats: diabetic and control animals on a 50% protein diet, which were untreated or treated with sorbinil. In these studies, diabetes was again associated with reduced body weight, but sorbinil had no influence on urinary urea nitrogen. Urinary albumin excretion, which was increased by diabetes, was not affected by sorbinil. GBM width was increased by diabetes, but in contrast to animals on 20% protein diets, the animals on 50% protein diets and treated with sorbinil did not have reduced GBM widths. Mesangial volume fraction was greater in diabetic animals than in controls, and sorbinil largely prevented mesangial expansion in them. Surprisingly, the control animals on the 50% protein diet and given sorbinil had increased mesangial volume fraction compared with control rats on the same diet not given the drug. In these experiments, diabetes was associated with reduced mean arterial blood pressure and renal plasma flow. Filtration fraction was increased in diabetic rats, but glomerular filtration rate was no different from that of controls. The increased filtration fraction was due at least partly to the decreased colloid oncotic pressure in the diabetic rats. Sorbinil did not affect any of these physiological or functional parameters. Thus, sorbinil decreased the rate of mesangial expansion in severely diabetic rats on high-protein intake through other than hemodynamic influences. The mechanism whereby this occurred or whereby this drug caused mesangial expansion in normal animals on a high-protein diet was not explained by these studies.