- Previous results from the principle investigator's laboratory and other have shown that a rapid increase in mean arterial blood pressure inhibits salt and fluid reabsorption in the renal proximal tubule. The resulting increase in volume flow to the thick ascending limp of the loop of Henle provokes an increased sodium reabsorption and Na, k-ATPase activity to limit the increase in volume flow to the distal tubule and increase in Na-K-2Cl co- transporter. A defect in the proximal tubular or thick ascending limb of the loop of Henle (TALH) responses could be responsible for the reduced pressure natriuresis that is that is the hallmark of hypertension. The overall goal of the research is to test the hypothesis that the """"""""downstream shift"""""""" of sodium reabsorption from proximal tubule (PT) to the TALH during acute hypertension is due to inhibition of PT sodium transporters, specifically NHE-3 and Na, K-ATPase), and that similar changes are evident in chronic genetic hypertension. There are three specific aims.
Specific Aim 1 aims to determine the cellular mechanisms responsible for the decrease in proximal tubular sodium transport during acute hypertension. The principal investigator will investigate the mechanism of sodium pump inhibition and whether or not apical sodium transporters are themselves inhibited or move to sub-apical endosomal compartments.
Specific Aim 2 is to determine the cellular mechanisms responsible for the increase in TALH sodium transport during acute hypertension Four questions will be addressed, namely, what is the mechanisms for sodium pump activation; is NHE-3 and/or NKCC2 activated or moved to the apical membrane; does a change in volume flow without hypertension activate sodium pump activity; and is cytochrome P450 arachidonic acid metabolism required for the response? Specific Aim 3 is to test the hypothesis that the cellular mechanisms responsible for the downstream shift in sodium reabsorption during acute hypertension are evident in genetic models of hypertension. For these studies, the principal investigator will use spontaneously hypertensive rats known to have defective proximal tubular sodium transport regulation, and Milan hypertensive rats known to have elevated thick ascending limp Na, K- ATPase.
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