There is increasing evidence that cytochrome P-450 monoxygenase derived arachidonate metabolites may play significant roles in renal hemodynamics and renal tubular transport. In nonrenal tissues, various of these compounds have been found to be potent vasodilators, to increase free intracellular calcium and to serve as secretagogues for peptide hormones. Arachidonic acid is also a substrate for the P-450 system in the kidney. Although recent studies have investigated the intracellular mechanisms by which cyclooxygenase and lipoxygenase derived metabolites of arachidonate acid elicit biologic responses, the intracellular signal transduction of P-450 arachidonate metabolites has not been well characterized. This project will utilize cultured cells of renal origin to screen the P-450 arachidonate metabolites in order to determine which compounds affect ion flux. Studies will then examine specific transport processes and the underlying intracellular signalling process. Specific questions that will be addressed are 1) whether the cellular effects of P-450 arachidonate metabolites are mediated by interaction with specific plasma membrane receptors and whether there is coupling to a guanine regulatory protein; 2) what the intracellular signals are by which the response to the P-450 metabolites is mediated. 4) the role of cyclic nucleotides and phosphatidylinositol hydrolysis; 4) the role P-450 metabolites themselves play as second messengers for the signal transduction of peptide hormones in the kidney. Studies will investigate whether the P-450 metabolites known to inhibit Na+ transport and act as vasodilatory agents are involved in the signal transduction of atrial natriuretic factor or bradykinin. Studies will also examine whether biologic effects of angiotensin II or vasopressin are influenced or mediated by endogenous generation of P-450 metabolites. By the use of cell suspensions or cultured cells from the glomerulus, proximal and distal nephron, a more complete understanding of both the factors regulating production of the P-450 arachidonate metabolites in the kidney and the responses of different nephron segments to these endogenously produced compounds will be attained.
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