Aldose reductase is implicated in the pathogenesis of diabetic cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for restoration of lens physiology. In the present study, the effect of aldose reductase inhibition subsequent to stage I cataract formation was investigated in the streptozocin-induced diabetic rat. Our results indicated that the aldose reductase inhibitor sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process despite continuation of hyperglycemia and elevated lens glucose. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process included: normalization of lens sorbitol, gradual recovery of existing fiber contour and interdigitation, production of new fibers, and partial restoration of lens myo-inositol content.

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SUMMARYAlthough enhanced activity of the polyol pathway has been implicated in the pathogenesis of certain complications of diabetes, evidence that aldose reductase activity and sorbitol content are increased in the characteristic tissue site of the diabetic renal lesion has been lacking. We therefore measured polyols in glomeruli isolated from control and streptozotocin-diabetic rats, and assessed whether changes in diabetic glomeruli could be prevented by oral administration of the aldose reductase inhibitor sorbinil. Compared with control, polyol content of glomeruli isolated from diabetic rats was increased 10-fold and fourfold at 6 and 9 wk, respectively, after induction of diabetes, but was unchanged in glomeruli from rats treated with sorbinil throughout the experimental periods. In contrast, glomerular myo-inositol content was reduced in diabetic samples; this fall in myo-inositol levels was also completely prevented by sorbinil. These results establish that glomeruli contain aldose reductase activity and provide the first demonstration that glomerular polyol content increases while myo-inositol content decreases in diabetes and that oral sorbinil prevents these changes despite persistent hyperglycemia. DIABETES 33:604-607, June 1984.T he enhanced activity of the polyol pathway, wherein the enzyme aldose reductase converts glucose to sorbitol, that occurs in hyperglycemic states has been implicated in the pathogenesis of certain complications of diabetes. These include cataracts, 12 peripheral neuropathy, 34 and, most recently, retinopathy. ductase activity and sorbitol content are increased in the characteristic tissue site of the diabetic renal lesion has been lacking. Aside from a report describing immunohistochemical identification of aldose reductase in renal cortical podocytes 6 and in human diabetic glomeruli, 7 and a communication indicating that renal cortex of galactosemic rats contains increased galactitol, 8 little is known about glomerular polyol metabolism and its changes in diabetes. If there is a causal link between polyol accumulation and diabetic nephropathy, then aldose reductase activity should be demonstrable in glomerular tissue and the glomerular polyol content should be elevated in diabetes. In the present study, we therefore measured polyols in glomeruli isolated from control and diabetic rats, and assessed whether changes in diabetic glomeruli could be prevented by oral administration of the aldose reductase inhibitor sorbinil. The results presented herein establish that normal glomeruli contain aldose reductase activity, and provide the first evidence that glomerular polyols increase in diabetes and that oral sorbinil prevents polyol accumulation in this tissue despite persistent hyperglycemia. MATERIALS AND METHODSAge-matched male white rats, separated into three groups and provided water ad libitum, were used in all experiments. Control animals received standard powdered laboratory chow. Diabetes was induced by a single injection of streptozotocin (65 mg/kg body wt) into the...

Proteinuria was diminished by concomitant oral administration of sorbinil, an aldose reductase inhibitor to streptozotocin-induced diabetic rats. Animals were placed in one of three groups: control, diabetic, sorbinil-treated diabetic. For a period of 10 weeks, 24-hour urine samples were analyzed weekly for volume, glucose, ketone, total protein (Pesce-Strande) and individual protein components having molecular weights between 15,000 and 120,000 daltons. The latter were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that controls excreted albumin (68,000 daltons) and low-molecular weight proteins between 15,000 and 20,000 daltons. Throughout the 10-week period of diabetes, there was a 7- to 12-fold increase in total urinary protein excreted in 24 h. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins having molecular weights of 30,000–100,000 daltons and an increase amount of albumin. Sorbinil treatment prevented approximately 70% of the increase in total protein excretion despite persistent hyperglycemia, glycosuria and ketonuria. Laser densitometric analysis indicated that the aldose reductase inhibitor decreased by 70% the excretion of newly detected proteins and albumin while maintaining the 15,000- to 20,000-dalton proteins. These results suggest that the polyol pathway is implicated in diabetic-induced proteinuria and inhibition of aldose reductase may represent a therapeutic approach for management of diabetic nephropathy.

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