MOLECULAR MECHANISMS OF EPITHELIAL SODIUM CHANNEL REGULATION

Yale University, New Haven CT

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Abstract

The amiloride-sensitive epithelial sodium channel (ENaC) mediates the final event in the reabsorption of sodium by the kidney. The activity of these channels determines the amount of sodium retained by the kidneys hence, ENAaC has a fundamental role in the maintenance of extra- volume and blood pressure. Many stimuli modulate the activity and expression of ENaC in the kidney but among them, aldosterone is the single most important one. There are two aims in this research proposal. The first one is to study one of the mechanisms that mediate the aldosterone-induced activation of ENaC in the distal nephron by a novel serine/threonine kinase known as sgk. Specifically, we proposal to investigate whether sgk is i) necessary and sufficient to mediate the aldosterone response in epithelial cells, ii) to elucidate the mechanism(s) triggered by sgk that results in activation of ENaC, iii) to find proteins that associated with sgk that may constitute substrates of the kinase or regulatory proteins, and iv) to generate animal models (transgenic mice) that exhibit decreased or increased activity of sgk selectively in the principal cells of the distal nephron. The design of the research allows us to obtain and correlate data from cells in culture, in kidney, and in whole animals. In the second aim of the proposal we will investigate the molecular mechanisms of one human mutation in the gene of the gamma subunit of ENaC that produces pseudohypoaldosteronism type 1. These studies will contribute to further elucidate the structure-function of ENaC channels.