Arachidonate metabolites participate in the modulation and mediation of renal hemodynamic, excretory, and endocrine function. Thus, they can alter: renal resistance, (redistribute) blood flow distribution, renin secretion and electrolyte and water excretion. Numerous renal disease states appear to involve an alteration in arachidonate metabolism. This proposal focuses on the site, identification, and modulation of arachidonate metabolism (i.e. prostaglandins, prostacyclin, thromboxane and lipoxygenase metabolite production) in animals with renal damage including ureter obstruction (hydronephrosis), renal venous constriction, glycerol-induced acute tubular necrosis, and renal artery stenosis. Our experiments will be performed with cortical and medullary microsomal incubations, with isolated perfused kidneys and with intact animals. We plan to determine the relationship between peptide recognition sites, arachidonate metabolism, cyclic nucleotides and renin in the renal cortex. Our studies (including tissue culture) will also focus on the hypothesis that a proliferation of renal cortical fibroblasts and an invasion by monocytes may mediate the exaggerated prostaglandin production associated with and partially modulating certain occlusive renal diseases. We also plan to characterize the biochemical and biological impact of the reversal of ureteral obstruction. Finally, we have discovered and propose to characterize a novel family of 22-carbon prostaglandins that, because of their restricted precursor availability and metabolic enzymes, can be largely limited to the renal medulla, where they may exert a critical regulatory function. We will pharmacologically manipulate the arachidonate pathway for the ultimate therapeutic development of new strategies for the treatment of renal diseases.
