CYTOCHROME P450 DEPENDENT ARACHIDONATE METABOLITES AND HYPERTENSION

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This project aims at defining the mechanism by which vasoactive hormones, oxygenases and cytokines interact within the kidney - at organ, cellular and molecular levels - to regulate renal function through arachidonate (AA) products generated by cytochrome P450-dependent monooxygenases. These studies will provide information relevant to understanding some of the pathophysiological mechanisms of hypertension, and may provide a rational basis for novel treatments. Preliminary findings show that P450-derived hydroxyeicosatetraenoic acids (HETEs) are released into urinary and venous effluents of isolated perfused kidneys and that the profile of 16-; 17; 18-; 19- and 20- HETE varies in the venous and urinary compartments. In addition, vasoactive hormones such as angiotensin II (AII) stimulate the release of HETEs. The biological profile of subterminal HETEs suggests that these P450-AA metabolites modulate renal transport function and vasomotion in a stereospecific manner. Further, AII stimulates the production of cytokines (TNF) resulting in enhanced prostaglandin E2 production by thick ascending limb of the loop of Henle (mTALH) tubules. The goals of the research are: (a) to examine the effect of vasoactive hormones on the profile of P450-derived eicosanoids released from normal kidneys and kidneys subjected to various experimental perturbations, (b) to characterize the activity of P450-AA products on vascular and renal tubular preparations, (c) to determine the relative contribution of preformed/stored P450-eicosanoids versus de novo synthesis of such eicosanoids in the renal response to vasoactive hormones, (d) to explore interactions among vasoactive hormones, TNF production, nitric oxide and synthesis of cyclooxygenase- and P450-derived eicosanoids in mTALH tubules.