title: Variable transcriptional regulation of the human aldosterone synthase gene causes salt-dependent high blood pressure in transgenic mice.
abstract: 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.
  
  
  
  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 this study. Our results show increased adrenal and renal expression of hCYP11B2 in transgenic mice with Hap-I when compared with mice with Hap-II. Importantly, we observed increased baseline blood pressure in Hap-I transgenic mice, an effect accentuated by a high-salt diet. Pathophysiological effects of elevated aldosterone were corroborated by our results showing upregulation of proinflammatory markers in renal tissues from the transgenic mice with Hap-I.
  
  
  
  These findings characterize the haplotype-dependent regulation of the hCYP11B2 gene where -344T serves as a reporter polymorphism and show that Hap-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Brahmaraju
authors.initials: B
authors.lastname: Mopidevi
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Meenakshi K
authors.initials: MK
authors.lastname: Kaw
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Ponnala
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Sudhir
authors.initials: S
authors.lastname: Jain
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Anita
authors.initials: A
authors.lastname: Rana
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Narsimha R
authors.initials: NR
authors.lastname: Keetha
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Sadik A
authors.initials: SA
authors.lastname: Khuder
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.).
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: From the Department of Physiology and Pharmacology (B.M., M.K.K., N.P., M.P., S.J., A.R., N.R.K., A.K.) and Department of Medicine (S.A.K.), College of Medicine, University of Toledo, OH; and Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH (S.N.F.). ashok.kumar2@utoledo.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017673:Sodium Chloride, Dietary / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D017673:Sodium Chloride, Dietary; D019405:Cytochrome P-450 CYP11B2
keywords: aldosterone; gene expression regulation; genetics; renin–angiotensin system