Zopolrestat prevention of proteinuria, albuminuria and cataractogenesis in diabetes mellitus.

The aldose reductase inhibitor, Zopolrestat, reduced proteinuria and albuminuria in streptozocin-induced diabetic rats compared with both untreated diabetic and age-matched controls. Daily administration of Zopolrestat (100 mg/kg) for 4 months decreased 24 h total protein excretion to 15.07 +/- 2.17 mg from 49.97 +/- 7.94 mg/day in untreated diabetic rats. Zopolrestat protected against excretion of any array of urinary 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/day), a 6-fold increase in urinary protein excretion compared to age-matched nondiabetic controls (11.65 +/- 1.71 mg/day). Zopolrestat treatment for 6 months produced therapeutic effects in the lens: transparency and myo-inositol content were maintained and lens sorbitol diminished, 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 values in age-matched controls; the ouabain-insensitive component increased by 63.6%. Zopolrestat treatment prevented these diabetic-induced changes and maintained ouabain-sensitive and ouabain-insensitive Rb influx. Collectively, these results suggest that Zopolrestat exerts a protective effect on the slowly developing diabetic cataract, as well as reducing albuminuria and proteinuria.