STZ-Induced Diabetes Results in Decreased Activity of Glomerular Cathepsin and Metalloprotease in Rats

IDDM in humans and STZ-induced diabetes in rats are both characterized in the early phase of the disease by glomerular hypertrophy; and, in the chronic phase of the disease, by mesangial expansion and glomerular basement membrane thickening. Decreases in glomerular intracellular protein degradation rates in diabetic individuals could contribute to the glomerular hypertrophy by allowing a build-up of cellular protein. Decreases in extracellular protease activity could contribute to the build-up of matrix protein in the mesangium and glomerular basement membrane. In this study, the levels of lysosomal cathepsin activities and glomerular metalloprotease activities were measured in isolated glomerular homogenates from STZ-induced diabetic rats at 4 days and 5 wk after administration of the drug. Some of the rats in the 5-wk study were treated with daily insulin; others were untreated. After 4 days of diabetes, cathepsin B and L activities were decreased by 15–45% when correlated with the levels of glomerular protein or DNA. Glomerular metalloprotease activity was decreased by 75% in the diabetic rats when compared with controls. After 5 wk of diabetes, cathepsin activities either were unchanged (for cathepsin B and L together or cathepsin S) or increased (cathepsin B alone) in insulin-treated diabetic rats, and continued to be decreased in untreated diabetic rats. A 40–50% decrease in glomerular metalloprotease activity continued in both diabetic groups. These data strongly suggest that decreases in the lysosomal cathepsin activities may contribute to IDDM-induced glomerular cellular hypertrophy. The data further indicate that a decrease in glomerular metalloprotease activity may contribute to diabetes-induced mesangial expansion and glomerular basement membrane thickening. The decrease in glomerular metalloprotease activity may be attributable to a decrease in metalloprotease synthesis or to an increase in endogenous tissue inhibitor of metalloprotease.