The polyol pathway, sorbinil, and renal dysfunction

Abstract

Nephropathy is a serious complication of Type I or insulin-dependent diabetes mellitus (IDDM) with a poor prognosis after the onset of proteinuria. Since aldose reductase may be implicated in the pathogenesis of proteinuria, onset and reversal studies were performed with sorbinil at a dose of 20 mg/kg to determine whether inhibition of this enzyme promoted either diminution or reversal of the appearance of urinary proteins. In the onset study, age-matched control, streptozotocin-diabetic, and sorbinil-treated diabetic rats were maintained for ten weeks; their 24-hour urine samples were analyzed weekly for volume, glucose, ketones, total protein, and individual protein components with molecular weights between 15,000 and 120,000 daltons. These last were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that sorbinil administered daily for ten weeks effectively diminished total protein excretion throughout this period primarily by protecting against appearance of abnormal urinary proteins that characterized the untreated diabetic state; the latter exhibited albuminuria, numerous newly detected proteins between 30,000 and 65,000 daltons, and an additional 4 to 5 proteins between 70,000 and 120,000 daltons. These findings closely resembled protein patterns exhibited by 54-week spontaneously diabetic BB rats, another model for IDDM. In the reversal study, age-matched control and streptozotocin-induced diabetic rats were maintained for four weeks, and weekly 24-hour urine analyses were performed as previously described. Results indicated that four-week diabetic rats excreted urine containing elevated glucose, ketones, and 3 to 5 newly detected proteins both higher than albumin in molecular weight (70,000 to 100,000 daltons) and lower than albumin in molecular weight (30,000 to 65,000 daltons) in marked contrast to the controls, which exhibited only albumin and low-molecular-weight proteins (≤20,000 daltons). To alter the course of proteinuria, sorbinil 20 mg/kg was administered at four weeks of diabetes. Sorbinil halted the progression of proteinuria and restored protein patterns toward the normal state over a subsequent nine-week period. After 13 weeks of diabetes, only 1 to 2 proteins remained both greater than albumin in molecular weight (70,000 to 94,000 daltons) and lesser than albumin in molecular weight (50,000 to 65,000 daltons). These results suggest that the polyol pathway is implicated in proteinuria and inhibition of this enzyme may represent a therapeutic approach to diabetic nephropathy.