Renal microsomal cytochrome P-450 catalyzes the in vitro and in vivo oxygenated metabolism of arachidonic acid to products that include epoxyeicosatrienoic acids (EETs), 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-OH-AA). The potential significance of this branch of the arachidonate cascade to renal function has been suggested by a) the potent biological activities of some of its metabolites, b) the demonstration of endogenous, enantioselective, formation of EETs, c) the regulation of the enzymes involved and/or of its metabolites by dietary salt loading, DOCA administration or by experimental hypertension and, d) the preferential expression of the cytochrome P-450 4A2 gene in hypertensive (SHR) rats. More recently, the demonstration of EETs as endogenous constituents of human kidney and urine and their increased urinary excretion during pregnancy induced hypertension suggest that this pathway may fulfill a yet unidentified role in human kidney physiology and/or pathophysiology. As part of a multidisciplinary effort to approach experimentally these important questions and, in support of projects 1-6, Core B will apply standard and established methods of eicosanoid extraction, purification, HPLC, GC/MS, protein immunoblotting and, cDNA purification and documentation to the identification, characterization and quantification of the enzymes and the metabolites of this branch of the arachidonate cascade.
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