It is now recognized that arachidonic acid metabolites of the kidney CYP450 monooxygenases are important regulators of renal vascular and tubular function. Kidney CYP450 metabolites play key physiological roles in the control of salt and water balance and the pathophysiology of organ disease. The long-term objective of this research project is to test the general hypothesis that CYP450 controlled generation of specific eicosanoids provides important mediators of renal microvascular function. Others and we have established that CYP450 epoxygenase and hydroxylase metabolites play a very important role in influencing afferent arteriolar function. Previous studies have found that CYP450 epoxygenase metabolites produced by the endothelium have anti-hypertensive properties and proposed that 11,12- EET and 14,15-EET are endothelium-derived hyperpolarizing factors (EDHFs) in the renal microcirculation. On the other hand, the CYP450 hydroxylase metabolite, 20-HETE, is produced by renal vascular smooth muscle cells, causes vasoconstriction and has been implicated as a pro-hypertensive factor. We will extend these initial findings by performing studies to provide a molecular and mechanistic description of the role of CYP450 arachionate metabolites in renal microvascular function. We will determine the cell singaling pathways and membrane currents involved in the renal myocyte responses to 11,12-EET and 14,15-EET and 20-HETE. We will also determine CYP450 metabolites role in hormonal and paracrine regulation of the preglomerular renal microvasculature. Lastly, we will determine the afferent arteriolar phenotypic alterations induced by genetically controlled changes in CYP450 activity. Taken together, this project will integrate current knowledge of the functional significance of the renal microvascular CYP450 pathway with advances in biomolecular approaches to describe the mechanism of action of 11,12-EET and 14,15-EET and 20-HETE and the physiological and/or pathophysiological importance of this pathway.
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