ABSTRACT
Differences in the type and extent of diabetic glomerular injury occur in rats made diabetic with streptozotocin (STZ) and in a spontaneously diabetic rat model of the BB/Wor strain. The diabetes prone (BB/DP) rat develops no mesangial matrix expansion with diabetes, whereas the STZ-treated Sprague Dawley rat does. The present study was performed to determine if glomerular metalloprotease activities were decreased in these two rat models of diabetes. Rats were studied at 8 weeks following the onset of hyperglycemia. All diabetic rats were maintained moderately hyperglycemic (plasma glucose = 350 mg/dL) with daily injection of insulin. Glomerular preparations were made and metalloprotease activities were assayed by hydrolysis of gelatin. Metalloprotease activities were decreased by 40-50% in STZ-treated Sprague Dawley rats, but not in BB/DP rats or diabetes resistant rats (BD/DR--the control for the BB/DP) made diabetic by STZ-injection. These data suggest that the decrease in glomerular metalloprotease activity may contribute to mesangial matrix expansion in the diabetic Sprague Dawley rats.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Type 1/enzymology , Kidney Glomerulus/enzymology , Metalloendopeptidases/analysis , Analysis of Variance , Animals , Body Weight , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Disease Models, Animal , Insulin/therapeutic use , Kidney/pathology , Male , Organ Size , Rats , Rats, Inbred BB , Rats, Sprague-DawleyABSTRACT
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.(ABSTRACT TRUNCATED AT 250 WORDS)
