Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats.

Recent studies suggest that decreased extracellular matrix (ECM)-protein degradation may contribute to the progressive mesangial matrix expansion that characterizes diabetic glomerular injury. Tissue inhibitors of metalloproteinases (TIMP) constitute a family of proteins that bind to and inactivate extracellular proteases and thus may serve to lower ECM protein degradation. Accordingly, the aim of this study was to determine whether there was an increase in TIMP-1 protein in the glomeruli of diabetic rats. Studies were performed in age-matched normal rats (C) and rats that received Streptozotocin (60 mg/kg IV) (Sigma Chemical Co., St. Louis, MO). A first group of diabetic rats (D) received daily injections of insulin to maintain moderate hyperglycemia (15 to 22 mmol/L). A second group of diabetic rats (D-Rx) received insulin injections twice daily to normalize blood glucose (3 to 7 mmol/L). Western blot analysis of glomerular proteins showed that there was an early increase in TIMP-1 expression during the rapid phase of glomerular hypertrophy that follows the onset of hyperglycemia. The increase in TIMP-1 expression was ameliorated by insulin treatment that normalized blood glucose levels. Six wk after the onset of hyperglycemia, the increase in TIMP-1 expression in glomeruli was sustained. These studies suggest that an early increase in TIMP-1, a protein that decreases extracellular metalloproteinase activity, may contribute to a decrease in ECM protein degradation in the diabetic glomerulus.