ZOPOLRESTAT PREVENTION OF PROTEINURIA, ALBUMINURIA AND CATARACTOGENESIS IN DIABETES-MELLITUS

The aldose reductase inhibitor, Zopolrestat, reduced proteinuria and a lbuminuria in streptozocin-induced diabetic rats compared with both un treated diabetic and age-matched controls. Daily administration of Zop olrestat (100 mg/kg) for 4 months decreased 24 h total protein excreti on of 15.07 +/- 2.17 mg from 49.97 +/- 7.94 mg/day in untreated diabet ic rats. Zopolrestat protected against excretion of an array of urinar y proteins with molecular weights between 30 and 100 kD, These effects were sustained throughout the 5th and 6th months of treatment. At the end of 6 months, Zopolrestat-treated diabetic rats excreted 22.77 +/- 4.39 mg/day compared to untreated diabetic rats (67.05 +/- 14.03 mg/d ay), a 6-fold increase in urinary protein excretion compared to age-ma tched nondiabetic controls (11.65 +/- 1.71 mg/day). Zopolrestat treatm ent for 6 months produced therapeutic effects in the lens: transparenc y and myo-inositol content were maintained and lens sorbitol diminishe d, despite elevated lens glucose, In contrast, untreated diabetic rats had opaque lenses which exhibited a 40-fold increase in sorbitol and myo-inositol depletion. In opaque lenses, ouabain-sensitive Rb influx, an index of Na-K-ATPase activity, decreased to only 53.8% of mean val ues in age-matched controls; the ouabain-insensitive component increas ed by 63.6%. Zopolrestat treatment prevented these diabetic-induced ch anges and maintained ouabain-sensitive and ouabain-insensitive Rb infl ux. Collectively, these results suggest that Zopolrestat exerts a prot ective effect on the slowly developing diabetic cataract, as well as r educing albuminuria and proteinuria.