Angiotensin II (angII) is a major hormone that regulates blood pressure and sodium retention. Its mechanisms of action are incompletely understood at the cellular level, in part because of pharmacological and molecular heterogeneity of angII receptors. Based on molecular and pharmacological data two major subclasses are distinguished: AT1 receptors are highly sensitive to biphenylimidazoles (e.g., losartan), while AT2 receptors are sensitive to tetrahydro-imidopyridines (e.g.., PD 123177, PD123319). Renal AT receptors are important fore regulation of the pressure natriuresis relationship by angiotensin. Pharmacological finger-printing of angII receptors and of angII regulation of electrolyte and fluid reabsorption in the proximal tubule indicate roles for AT1 and AT2 receptors. While the role of AT1 receptors is well established, importance of AT2 receptors has been recognized only recently. While the role of AT1 receptors is well established, importance of AT2 receptors has been recognized only recently. We hypothesize that AT2 receptors, although not the dominant type in the proximal tubule, are responsible for diminished salt and fluid reabsorption that is observed at high physiological angII concentrations. To directly test this hypothesis and study the signaling mechanisms and target transporters for AT2 receptors, we propose to isolate well differentiated proximal tubule cell lines from mouse models that lack either AT1 or AT2 receptors. These cell lines will be accomplished by crossing available AT-""""""""knock-out"""""""" mouse models with an """"""""immortomouse"""""""" that carries a temperature- sensitive mutant of the immortalization gene SV40 large T antigen. Proximal tubule cell lines will be isolated by expansion of microdissected tubules in culture under permissive conditions (T antigen expressed). Differentiation of these epithelial cells will be induced by a shift of cells to non-permissive conditions (T antigen suppressed). These cell lines, grown under conditions of high differentiation (confluent, electrically resistant monolayers), will be used to quantitatively assess angII effects on overall Na bicarbonate reabsorption as well as key transporters (chloride conductance, apical Na/H exchanger, basolateral Na- bicarbonate cotransporter, Na, K-ATPase, K-conductance). We will also test the novel hypothesis that a tyrosine kinase signaling pathway is involved in the inhibition of NHE3 by AT2 and eicosanoids. Transport measurements will utilize real-time, on-line recordings, based on imaging of fluorescent indicator dyes of electrophysiology. These data should provide specific information about the effects and roles of the AT2 receptor, thus complementing available information on AT1 receptors and providing a much better overall understanding of angII actions on renal Na+ metabolism.
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