Pathophysiology of insulin-regulated renal blood flow and sodium excretion

Project Summary/Abstract Impaired regulation of renal blood flow (RBF) is recognized as a critical element in the pathologies of diabetes and metabolic syndrome through effects on glomerular pressure, GFR, and urinary sodium excretion (UNaV). The mechanism for impaired RBF regulation in these conditions is not known. We have evidence for a novel physiological effect of insulin on RBF that may translate to mechanisms for pathophysiological RBF impact. Our data suggest that preventing excess sodium loss after meals is the physiological function of insulin- regulated UNaV. This is not due solely to tubular sodium reabsorption, as the literature would predict. We show that insulin also exerts renal vasoconstrictor tone after meals, possibly via thromboxane (TXA2), that limits the degree of meal-induced renal vasodilation. Impairment, of that physiological function should cause excessive renal vasodilation after meals, causing renal salt wasting and potential long-term implications on the progression of CKD. Exaggeration of this physiological function should cause overt renal vasoconstriction, sodium retention, and hypertension if sustained. Additional data show that blocking the protective role of nitric oxide (NO) enables high-sucrose diet to cause hypertension, which we can prevent by blocking hyperinsulinemia. We will test the central hypothesis that: The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence that limits the degree of meal-induced renal vasodilation. Counterbalancing input from nitric oxide is required to prevent overt renal vasoconstriction and hypertension. The specific aims will test whether: Aim 1: The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence. The experiments will test the hypotheses that: a. Preventing the meal-induced increase in plasma insulin will cause greater and more sustained increases in RBF and greater UNaV than occurs in normal control rats. b. The insulin-dependent renal vasoconstrictor influence requires TXA2. c. Under conditions of background NOS inhibition, glucose bolus will cause overall renal vasoconstriction and amplified sodium retention. d. ENaC mediates the tubular reabsorption component of the acute sodium-conserving effect of insulin. Aim 2: Impaired NO synthesis causes insulin-dependent renal vasoconstriction and hypertension during high-sucrose intake. Experiments test the hypotheses that: a. NOS inhibition will enable chronic high-sucrose intake to cause hypertension (DSI telemetry, 24 hr/day). b. Blocking hyperinsulinemia will prevent the hypertensive response to high-sucrose intake. Restoring only intra-renal hyperinsulinemia restores the hypertension response. c. TXA2 synthase inhibition will prevent the hypertensive effect of chronic high-sucrose intake.