This proposal seeks support to continue studies utilizing a combination of complementary in vivo and in vitro strategies to further define the major regulatory determinants of renal fluid and solute exchange in health and disease. Studies in the previous funding period clearly implicate ANP, dopamine and bradykinin as potent modifiers of renal microvascular and tubule cell functions. In the next period for which support is requested we aim specifically to: 1) define the molecular mechanisms of ANP interaction with the renal medullary epithelial Na channel, a multimeric integral membrane protein recently purified to homogeneity in this laboratory; 2) determine the effects of ANP and bradykinin on apical and basolateral Na transport pathways in isolated perfused rat IMCD segments, where epithelial sidedness is preserved; 3) evaluate the importance of the endogenous ANP system in states of altered body fluid volume homeostasis (DOCA escape, rats with remnant kidneys and rats with nephrotic syndrome, congestive heart failure, and chronic hyperglycemia secondary to diabetes mellitus) utilizing rats made chronically ANP deficient by active anti-ANP immunization; 4) define both in vivo and in vitro the basis for reduced renal responsiveness to ANP in experimental nephrosis and congestive heart failure; and 5) characterize the cellular basis for dopamine-mediated inhibition of Na-K-ATPase in proximal tubule and the contribution that dopamine plays in mediating ANP's indirect inhibitory actio on proximal tubule Na transport. This combination of mutually-reinforcing in vivo and in vitro studies promises to extend our understanding of the mechanisms whereby several novel biologically active compounds regulate renal microvascular and tubule epithelial function in health and disease, the central goal of this grant since its inception in 1969.
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