The purpose of the experiments in this proposals is to determine the mechanism of abnormal renal hemodynamics in insulin- dependent diabetes mellitus in rats. It is thought that increased renal blood flow, glomerular filtration, and glomerular pressure contribute to the development of diabetic nephrosclerosis. Correcting the abnormal hemodynamics may prevent or ameliorate the nephrosclerosis. Several protocols are proposed. Because diabetes is associated with decreased intracellular myoinositol triphosphate (IP3), and this compound is important in regulation of intracellular calcium, we will normalize IP3 by treating diabetic rats with sorbinil, an inhibitor of aldose reductase. We will measure renal hemodynamics by clearance and micropuncture methods to determine whether aldose reductase inhibition corrects the hyperfiltration. In another protocol, normal rats will be fed a high galactose diet to produce galactosemia. This should also reduce intracellular IP3. Renal hemodynamics will be measured to determine whether hyperemia develops, as it does in diabetes. If it does, it would support the role of IP3 and aldose reductase in the mechanism of diabetic renal hyperemia. In other experiments, diabetic rats will be fed a sodium-deficient diet, as we have found that this can correct diabetic hyperfiltration. We will measure plasma volume, renin, atrail natriuretic factor (ANF) and correlated these with renal hemodynamics in order to determine the mechanism. Long-term studies will be carried out to determine whether dietary sodium restriction prevents renal pathologic changes of diabetes and proteinuria. Additional protocols will test whether contraction of renal vascular elements by exogenous calcium is mediated by one of the renal vasoactive hormone systems, or by a direct effect of calcium on vascular smooth muscle. The long-range goals of all of these studies is to elucidate the mechanism of diabetic hyperfiltration and to develop a therapeutic strategy that could be used in humans to correct the abnormal renal hemodynamics.
| Bank, N; Aynedjian, H S (1993) Role of EDRF (nitric oxide) in diabetic renal hyperfiltration. Kidney Int 43:1306-12 |
| Bank, N; Aynedjian, H S (1992) Role of thromboxane in impaired renal vasodilatation response to acetylcholine in hypercholesterolemic rats. J Clin Invest 89:1636-42 |
| Kaplan, R; Aynedjian, H S; Schlondorff, D et al. (1990) Renal vasoconstriction caused by short-term cholesterol feeding is corrected by thromboxane antagonist or probucol. J Clin Invest 86:1707-14 |
| Bank, N; Aynedjian, H S (1990) Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest 86:309-16 |
