This proposal will examine the role of P450 metabolites of arachidonic acid (AA) in the control of loop chloride reabsorption and tubuloglomerular feedback, and the contribution of this system to the development of hypertension in Dahl salt-sensitive (S) rats.The functional significance of changes in renal metabolism of AA by P450 in prehypertensive Dahl S rats in altering chloride reabsorption in the loop of Henle will be evaluated using in vivo tubular perfusion techniques.The effects of pharmacologic induction or inhibition of the renal metabolism of AA by P4504A isoforms with clofibrate or 17- octadecynoic acid (17-ODYA) on loop chloride transport and the development of hypertension in Dahl S rats will be evaluated. We will determine whether tubuloglomerular feedback responses are impaired in Dahl S rats, the role of changes in the renal metabolism of AA by P450 in altering this response, and whether subsequent elevations in glomerular capillary pressure contribute to the rapid progression of hypertensive glomerular injury in these animals. Finally, a genetic linkage analysis will be performed to determine whether the P4504A1 or 4A2 genotype cosegregates with the degree of hypertension or glomerular disease in F2 population of a cross between Dahl S and R rats. These studies combining molecular, cellular, biochemical, renal micropuncture and whole animal approaches should provide a unique integrative picture regarding the role of endogenous P450 metabolites of AA in the regulation of renal tubular and vascular function, and the contribution of this system to the development of hypertension and the progression of glomerular disease in Dahl S rats.
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