REGULATION OF SODIUM PUMPS IN THE KIDNEY

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Regulation of renal salt transport is essential to maintain extracellular volume and blood pressure. The objective of this proposal is to define the molecular mechanisms responsible for two key homeostatic natriuretic responses that occur in the proximal tubule (PT). 1) An acute increase in arterial pressure rapidly decreases PT salt and volume reabsorption, thereby increasing delivery to the macula densa, a key signal for autoregulation, and contributing to pressure natriuresis. This laboratory has demonstrated a redistribution of sodium pumps from surface to putative internal stores in this response. 2) A high salt diet provokes a chronic decrease in the fractional reabsorption of salt in the PT. This laboratory has demonstrated that Na,K-ATPase beta, but not alpha expression is decreased in this model. Both of these natriuretic responses are altered in hypertension. We will apply subcellular fractionation methods to identify surface and intracellular membranes and the change in the patterns of transporter abundance and activity in these pools in response to the natriuretic stimuli. Three hypotheses will be tested related to the objective. 1) Test the hypothesis that there are pools of Na,K-ATPase alpha beta heterodimers and NHE in both surface and intracellular membranes in renal cells, as well as pools of alpha and beta subunits that are not assembled as alpha beta heterodimers; determine whether these intracellular pools can be recruited to the plasma membrane, and test putative mediators of the redistribution. 2) Test the hypothesis that the rapid decrease in PT sodium transport that accompanies an acute increase in arterial pressure is due to decreased surface expression and/or activity of sodium pumps and NHE exchangers. Determine the time course and reversibility of the response, test putative mediators of the response, and whether the response is altered in hypertension models. 3) Test the hypothesis that the rate of production of one of the Na,K-ATPase subunits limits the pool size of active sodium pumps expressed in the PT plasma membrane, and can limit sodium transport. Determine the response to high salt diet in control and hypertensive rats and whether antisense to alpha or beta also limits the production of sodium pumps. Accomplishing our objective will contribute to our understanding of how alterations in these natriuretic responses may be mechanistically involved in the generation or maintenance of hypertension.