The corticosteroid aldosterone is a major activator of Na+ reabsorption in tight epithelia which acts primarily on the apical amiloride-blockable Na+ channel. Our long term objective is to reveal and characterize the cellular events by which this hormone mediates its natriferic actions. In particular we intend to test the hypothesis we have recently formulated. According to this hypothesis, the early response to the hormone is the activation of pre-existing channels mediated by the mineralocorticoid receptor, while its chronic effect is de-novo channel synthesis induced by occupancy of the glucocorticoid receptor. The current application aims to use channel activity measured in cells and isolated membranes, binding assays of radioactive amiloride analogues, expression of functional channels in Xenopus oocytes injected with epithelial RNA and molecular cloning techniques to address the following issues: (1) To demonstrate that the short and long term actions of the hormone are specifically induced by mineralo- and glucocorticoids, respectively. (2) To determine which part of the natriferic action can be correlated with an increase in amiloride binding and enhanced expression in oocytes. (3) To investigate candidate mechanisms for the activation of pre-existing channels by aldosterone. (4) To clone aldosterone induced proteins and in particular the one that evokes channel activity in oocytes, using subtracted cDNA probes and functional expression. Na+ reabsorption across tight epithelia is an essential process for the maintenance of body electrolyte and water homeostasis. Abnormalities in this process are known to cause kidney disorders and hypertension. Aldosterone is the major regulator of Na+ reabsorption in all vertebrates. A better understanding of the elaborate mechanisms by which this hormone mediates its action, is of basic physiological importance, and clinical significance.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Physiology Study Section (PHY)
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Weizmann Institute of Science
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