The kidney play a central role in the control of body fluid and composition. The cytochrome P450 (P450)- dependent arachidonic acid (AA) monooxygenase is now recognized as a component of the biomedically important AA cascade. Abundant literature data implicate P450-derived eicosanoids in various aspects of kidney function, as well as in the pathophysiology of experimental hypertension. However, the mostly descriptive nature of these studies and a paucity of appropriate experimental tools has precluded unequivocal assignments of specific functions and/or mechanisms of action to the P450 eicosanoids, as well as current on progress in the characterization of kidney P450s, to offer an integrated molecular, biochemical, biophysical and functional approach to the delineation of the physiological and/or pathophysiological significance of the renal AA monooxygenase. Metabolites, isoform specific inhibitors, cloned cDNAs and/or genes, and recombinant DNA methods will be utilized for the molecular characterization of P450-isoform specific phenotypes at the cellular, organ and whole animal levels. Functional studies will include: a) biochemical documentation of P450 isoform specific changes in cell or whole animal AA metabolism b) characterization of cellular phenotypes including hormonal responses, signaling mechanisms and ion flux and channel effects, c) the identification and characterization of hemodynamic and/or tubular effects, and d) the use of mice strains with mutated P450 genes for the integration of gene specific cell and/or organ phenotypes into whole animal physiology and/or pathophysiology. The long term goals of this project are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answer to these important questions are needed for the development of meaningful approaches to: a) the unequivocal definition of their pathophysiological significance, and b) subsequent pharmacological and/or clinical interventions.
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