Cytochrome P4504A genotype cosegregates with hypertension in Dahl S rats

Recent studies indicate that the production of 20-HETE by a P4504A2 enzyme in the outer medulla of the kidney is reduced in Dahl salt-sensitive (SS/Jr) rats, but the contribution of this abnormality to the elevation in loop Cl- transport and development of hypertension in this model is unknown. THe present study found that alleles at the locus for the P4504A2 gene cosegregate with blood pressure in an F2 population (n=151) derived from a cross between SS/Jr and Lewis rats (P < .0001). The P4504A2 locus is located in a region on rat chromosome 5 where a blood pressure quantitative trait locus was previously detected. Systolic blood pressure averaged 201 +/- 6 mm Hg in rats with the SS genotype (n=36), 192 +/- 4 mm Hg in SL genotype rats (n=77), and 169 +/- 3 mm Hg in LL genotype rats (n=38). In further studies, we confirmed that there are phenotypic differences in the expression of the P4504A2 gene in the kidneys of SS/Jr and Lewis rats. Although the production of 20-HETE from 14C-arachidonic acid was similar in microsomes prepared from the renal cortex of SS/Jr and Lewis rats (54 +/- 3 versus 55 +/- 3 pmol/min/mg protein), the production of 20-HETE in microsomes prepared from the outer medulla (OM) was markedly reduced in SS/Jr rats (2.8 +/- 0.8 versus 6.7 +/- 1 pmol/min/mg protein). The diminished production of 20-HETE in the OM was due to a threefold reduction in the level of P4504A2 protein. These results suggest that an altered expression of the P4504A2 enzyme in the OM may contribute to the development of hypertension in SS/Jr rats.