Variable Transcriptional Regulation of the Human Aldosterone Synthase Gene Causes Salt-Dependent High Blood Pressure in Transgenic Mice

Background—Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked -344T polymorphism in the human CYP11B2 (hCYP11B2) gene to human hypertension. hCYP11B2 gene promoter has 3 single-nucleotide polymorphisms in linkage disequilibrium: T/A at -663, T/C at -470, and C/T at -344. Variants ACT occur together and form the haplotype-I (Hap-I), whereas variants TTC constitute Hap-II. We hypothesize that these single-nucleotide polymorphisms, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. Methods and Results—We evaluated differences in tissue expression in vivo and consequential effects on blood pressure stemming from the 2 haplotypes. Novel transgenic mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either Hap-II or Hap-I variant are used in t...