Diabetic nephropathy is characterized by the presence of micro-albuminuria which in most patients progresses to the nephrotic syndrome. Studies of diabetic humans with microalbuminuria suggest that there is a functional and reversible component to this proteinuria which is exacerbated acutely by exercise and can be ameliorated by continuous insulin infusion for only 1-2 days. A similar acute change in urinary albumin excretion can be produced by manipulation of dietary protein or converting enzyme inhibition in humans with diabetic nephropathy and in several animal models of nephrotic syndrome, including diabetes. The changes in albuminuria in each case are not due to a change in glomerular filtration rate and most likely are hormonally mediated. The reduction in proteinuria in nephrotic or diabetic rats after converting enzyme inhibition or restriction of dietary protein can be reproduced by specific inhibition of the enzyme responsible for degradation of bradykinin suggesting that the antiproteinuric effect of enalapril may be due in part to its effect to potentiate bradykinin activity. Abnormalities of the renal kallikreinkinin system, renin- angiotensin, and eicosanoid systems in diabetes have been reported, but the relationship of these abnormalities to the development of proteinuria in diabetes is unknown. The purpose of this proposal is to elucidate the possible role of changes in bradykinin activity in the glomerulus as a mediator of proteinuria in diabetes and to examine the interrelationship of this autacoid to renin activity and glomerular eicosanoid synthesis. Dietary protein, converting enzyme inhibitors and specific inhibitors of bradykinin and bradykinin degradation will be used to investigate the role of these autacoids, particularly bradykinin, in the development of proteinuria in diabetes, and the mechanisms by which dietary protein restriction and converting enzyme inhibition reduce proteinuria in diabetic rats.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Medical University of South Carolina
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