Recent studies indicate that cytochrome P450 metabolites of arachidonic acid (AA) play a critical role in regulation of renal tubular and vascular function and chronic control of blood pressure. Preliminary results showed that a gene of the cytochrome P4504A family is differentially expressed in the kidney of Dahl S and Lewis rats and that this gene cosegregates with the development of hypertension in an F2 cross of these two strains. To explore this system's role in regulation of renal function and development of hypertension, congenic strains of rats were developed in which overlapping segments of chromosome 5 of the Lewis rat, that include or exclude the P4504A region, were introgressed into the Dahl S genetic background by selective backcross breeding. Using these congenic animals, we propose to determine whether P4504A genes play a causal role in modulating renal function and/or the development of hypertension in Dahl S rats by determining whether expression of P4504A enzymes in congenic strains of rats where P4504A alelles of normotensive Lewis rats have been introgressed into the Dahl S genetic background affect the development of hypertension and whether this manipulation alters pressure-natriuretic and tubuloglomerular feedback responses.
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