The long term objectives of this proposal are to understand in greater detail the pathways and regulatory mechanisms of ion transport across cell membranes. The research focusses on the renal collecting duct because this structure has developed specialized transport systems to regulate ion excretion. The regulation of Na and Cl excretion, for example, plays a central role in the regulation of blood pressure. Precise regulation of H+ and K excretion in order to match intake is critical for prevention of acidosis (or alkalosis) and hyperkalemia (or hypokalemia), respectively. The collecting duct has developed systems to regulate the absorption or secretion of each ion species. Specific experimental approaches outlined in the application will examine the extent to which hormones and autocoids produce effects on one or more transport systems. Collecting duct ion transport can be divided into two general categories: acid-base and Cl transport is effected by intercalated cells, and Na and K transport is effected by principal cells.
The specific aims of the application are to: a) investigate the mechanism(s) whereby cAMP and primary messengers stimulate H+ and HCO3 secretion by intercalated cells; b) determine the mechanisms where by hormones and autocoids alter Na and K transport by principal cells; and c) determine the linkage between oxidative phosphorylation and turnover of the Na-K pump in the K-K exchange mode. The methods to be used in the evaluation of these mechanisms include intracellular pH measurements, intracellular voltage measurements with equivalent circuit and cable analysis, tracer flux measurements, net transport measurements of Na, K, C1, and HCO3, and biochemical measurements in single nephron segments. The results will be relevant to our integrated understanding of salt and electrolyte balance. In addition, they will be important to the understanding of mechanisms of hormone action. Finally, the experiments may provide new insights regarding the ways the Na-K pump can be regulated both by hormones and by metabolism.
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