Angiotensin (AII) exerts a biphasic effect on Na reabsorption of kidney epithelial cells. Picomolar concentrations of AII promote Na reabsorption in the proximal tubule while nanomolar concentrations decreases reabsorption. The direct effects can be reproduced in vitro in tissue culture in our laboratory employing rabbit proximal tubule epithelial cells. We will test the hypothesis that a novel AII receptor exists on proximal tubular epithelial cells that is not coupled to phospholipase C, a major signal transduction pathway in other target tissues.
the aims of this proposal are to determine the precise mechanisms of signal transduction coupled to sodium transport in proximal tubular epithelium. We hypothesize that AII inhibits adenylate cyclase activity in the picomolar range, a signaling pathway that is responsible for AII-induced antinatriuresis. In addition, higher physiologic concentrations of AII stimulate phospholipase A2 and, thereby, release arachidonic acid that is metabolized by a cytochrome P450 isozyme to unique eicosanoids (epoxyeicosatrienoic acids, and dihydroxytrienoic acids. Thus a characterization of receptor, adenylate cyclase and phospholipase A2 regulatory mechanisms and the products of arachidonic acid metabolism as we propose, herein, is essential to development of a composite picture of signaling mechanisms that mediate changes in salt reabsorption. Techniques to be employed for quantative assessments of arachidonic acid and phospholipid metabolism include TLC, HP and GG/MS with cells in tissue culture and cells from animals with modulated AII level in vivo. These studies are important for understanding the action of AII on renal function and salt homeostasis. It is possible that these studies will elucidate additional mechanisms whereby AII contributes to blood pressure regulation and the pathophysiology of hypertension.
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