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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK043186-01
Application #
3244500
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-03-01
Project End
1995-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Brees, D K; Hutchison, F N; Cole, G J et al. (1996) Differential effects of diabetes and glomerulonephritis on glomerular basement membrane composition. Proc Soc Exp Biol Med 212:69-77
Imamura, A; Mackenzie, H S; Lacy, E R et al. (1995) Effects of chronic treatment with angiotensin converting enzyme inhibitor or an angiotensin receptor antagonist in two-kidney, one-clip hypertensive rats. Kidney Int 47:1394-402
Hutchison, F N (1993) Hormonal modulation of proteinuria in the nephrotic syndrome. Am J Nephrol 13:337-46
Hutchison, F N; Webster, S K; Jaffa, A A (1993) Altered renal kallikrein and renin gene expression in nephrotic rats and modulation by converting enzyme inhibition. J Clin Invest 92:1073-9
Ullian, M E; Hutchison, F N; Hazen-Martin, D J et al. (1993) Angiotensin II-aldosterone interactions on protein synthesis in vascular smooth muscle cells. Am J Physiol 264:C1525-31
Hutchinson, F N; Webster, S K (1992) Effect of ANG II receptor antagonist on albuminuria and renal function in passive Heymann nephritis. Am J Physiol 263:F311-8