Considerable evidence suggests that angiotensin (All) has direct effects on Na reabsorption of kidney epithelial cells. At lower physiological concentrations, All promotes Na reabsorption, while at high concentrations it decreases reabsorption. The direct effects can be reproduced in vitro in tissue culture employing rabbit proximal and distal tubule epithelial cells. This proposal is designed to investigate the cellular mechanism(s) by which All alters Na transport. Data from this laboratory demonstrates that in the proximal tubule All decreases cAMP levels and, therewith , probably increases Na/H exchange activity in the luminal plasma membrane promoting sodium reabsorption. In proximal and distal tubules, higher levels of All affect Ca2+ metabolism and eicosanoid production that may, in turn, decrease Na reabsorption.
The specific aims i nclude the following: 1) Establish the magnitude of sodium transport that is influenced by All and determine the temporal and dose-dependent correlations with decrements in cAMP of proximal and changes in eicosanoid and Ca metabolism of proximal and distal tubular regions of the nephron; 3) Determine the extent to which independent modulators of cAMP, eicosanoid biosynthesis and Ca metabolism mimic or potentiate the antinatriuretic and natriuretic actions of All; and 4) Determine the extent to which the """"""""positive feedback"""""""" response to All in proximal epithelium following prolonged exposure to high circulating All is mediated by modulation of All binding or enhanced signal transduction. The experimental approaches consist of (1) Correlation of the numbers and affinities of All receptors and modes of signal transduction with transport measurements employing isotope fluxes, fluorescence microscopy, and transcellular bioelectric measurements; (2) Use of additional manipulations that alter the level of second messengers; (3) Comparisons of All-dependent levels of intracellular messengers and transport responses between proximal and distal tubule; and (4) Comparisons of manipulations in All receptors and transport responses. These studies are important for understanding the actions of All on renal function and salt homeostasis; moreover, a new concept for primary regulation for All via adenylate cyclase is involved consistent with a novel class of All binding sites. Secondary actions on phospholipase A2 and Ca metabolism appear to mediate natriuresis. It is possible that this model will help to elucidate mechanisms whereby All contributes to the pathophysiology of high renin states such as cirrhosis, renal artery stenosis, and congestive heart failure.
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