INDUCTION OF RENAL KALLIKREIN AND RENIN GENE-EXPRESSION BY INSULIN AND IGF-I IN THE DIABETIC RAT

The renal kallikrein-kinin system and the renin-angiotensin system are implicated in the pathogenesis of diabetic nephropathy. We have shown that renal kallikrein and renin gene expression are altered by diabet es. To investigate the cellular mechanisms responsible for these chang es, we examined the effects of acute insulin and insulin-like growth f actor I (IGF-I) treatment on renal kallikrein-kinin and renin-angioten sin system components. Three weeks after induc tion of diabetes, we me asured renal kallikrein and renin mRNA levels, renal kallikrein and re nal renin activity, and plasma renin activity in control and diabetic rats and diabetic rats treated with insulin or IGF-I for 2 or 5 h. In diabetic rats, kallikrein and renin mRNA levels were reduced >50% comp ared with control rats. Renal tissue kallikrein levels and plasma reni n activity were decreased, whereas renal renin content was unchanged. Insulin increased kallikrein and renin mRNA levels after 2 h. IGF-I, a t a dosage that stimulated kallikrein mRNA levels in control rats, had no effect on renal kallikrein and renin content or mRNA levels in dia betic rats. However, infusion of a fivefold higher IGF-I dosage result ed in a two-to threefold increase in kallikrein and renin mRNA levels in 2 h. These data suggest that 1) diabetes suppresses kallikrein and renin gene expression, and these abnormalities are reversed by insulin or IGF-I; and 2) the diabetic state produces resistance to IGF-I indu ction of kallikrein and renin gene expression. These changes in regula ted synthesis of kallikrein and renin in the kidney may underlie renal vascular changes that develop in diabetes.