CYTOCHROME P-450 ARACHIDONIC ACID METABOLISM & REGULATION OF RENAL ION TRANSPORT

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It is now clear that certain arachidonate metabolites that derive from cytochrome P-450 (CP-450) metabolism have important effects on ion and water transport in the mammalian kidney. What is currently less clear is the physiologic and pathophysiologic importance of this pathway in regulating the kidney's contribution to salt and water balance. There are, however, a number of compelling observations which call for a thorough analysis of the functional significance of CP-450 arachidonate metabolism in the regulation of sodium reabsorption by the kidney. These observations are basically from models of experimental hypertension. In the spontaneously hypertensive rat (SHR), McGiff, Schwartzman, Abraham and their colleagues have implicated a role for omega and omega-1 hydroxylation of arachidonic acid in the development of hypertension. The functional link, however, remains unclear. In studies from our group, it appears that dietary salt loading markedly induces epoxygenase activity in the normal rat, but not in the Dahl salt-sensitive genetic strain of rat. Again, the functional link in the Dahl salt-sensitive animal has not been elucidated. Although data in hypertensive animal models provide a major impetus for studying the regulation of sodium transport by cytochrome P-450 metabolites, we are confident that these compounds will play an important role in the normal handling of sodium by the nephron. This project proposes four specific aims: (1) to identify and characterize the mechanism of action and functional significance of both CP-450 arachidonate metabolites that augment renal sodium retention and those metabolites that inhibit renal sodium reabsorption; (2) to test the hypothesis that cross-metabolism, i.e., metabolism of arachidonate by both the CP-450 pathway and the cyclooxygenase pathway, yields important biologically active metabolites which modify sodium transport by activating specific prostaglandin receptor sub-types; (3) to test the hypothesis that the proximal tubule and collecting duct serve as important sites for arachidonate cross- metabolism within the kidney; (4) to characterize the urinary excretion of CP-450 arachidonate metabolites in normal humans, normal humans on varying salt intake, patients with essential hypertension, and pregnant females with and without pregnancy-induced hypertension. These studies, in concert with the multi-discipline approach in this Program Project Grant, will define the importance of cytochrome P-450 arachidonate metabolism in the regulation of normal renal function and in alterations of renal function, that produce or result from hypertension.