Molecular variants in the P450c11AS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension.
Dahl salt-sensitive (S) and salt-resistant (R) rats are widely used to study genetic determinants of salt-sensitive hypertension. Differences in blood pressure under a high sodium diet in these two strains may be due to differences in the synthesis of 18-OH-11-deoxycorticosterone (18-OH DOC). This difference in 18-OH-DOC synthesis is due to mutations in the Dahl R rat's gene for P450c11 beta (11 beta-hydroxylase), an adrenal enzyme involved in the synthesis of both corticosterone and 18-OH DOC from 11-deoxycorticosterone. Aldosterone/renin ratios in plasma and in the adrenals are greater in Dahl S than R rats, suggesting an altered physiologic relationship between the renin-angiotensin and aldosterone systems between these strains. We demonstrate that the mRNA for P450c11AS, (aldosterone synthase), an enzyme required for aldosterone synthesis, is identical in the Dahl S rat and in normotensive Sprague-Dawley rats, but that P450c11AS mRNA from the Dahl R rat contains 7 mutations that result in two amino acid substitutions. These two changes result in a form of P450c11AS that has a greater apparent Vmax and lower apparent Km, resulting in an enzyme that catalyzes the conversion of 11-deoxycorticosterone to aldosterone at a greater rate in Dahl R rats than the P450c11AS in Dahl S rats or Sprague-Dawley rats. Although plasma and adrenal renin are lower in Dahl S versus R rats, the regulation of P450c11AS mRNA expression in rats fed a low and high salt diet are identical in these strains. The current findings may explain both the reduced aldosterone concentrations and increased aldosterone/renin ratios previously reported in the Dahl S versus Dahl R rat.
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C M
CM
Department of Obstetrics, University of California, San Francisco 94143-0556, USA.
Wang
J M
JM
St Lezin
E
E
Kurtz
T W
TW
Mellon
S H
SH
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000235:genetics*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase