Variable Transcriptional Regulation of the Human Aldosterone Synthase Gene Causes Salt-Dependent High Blood Pressure in Transgenic Mice. (February 2015)

• Record Type: Journal Article
• Authors: Mopidevi, Brahmaraju; Kaw, Meenakshi K.; Puri, Nitin; Ponnala, Madhusudan; Jain, Sudhir; Rana, Anita; Keetha, Narsimha R.; Khuder, Sadik A.; Fiering, Steven N.; Kumar, Ashok
• Is Part Of: Circulation. Volume 8:Number 1(2015)
• Publication Date: 2015-02
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000694
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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 <italic>CYP11B2</italic> (h<italic>CYP11B2</italic>) gene to human hypertension. h<italic>CYP11B2</italic> 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 h<italic>CYP11B2</italic> gene and affect blood pressure regulation.</p> </sec> <sec> <title>Methods and Results—</title> <p>We evaluated differences in tissue expression in vivo and consequential effects on blood pressure stemming from the 2 haplotypes. Novel transgenic mice with the h<italic>CYP11B2</italic> 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 h<italic>CYP11B2</italic> 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.</p> </sec> <sec> <title>Conclusions—</title> <p>These findings characterize the haplotype-dependent regulation of the h<italic>CYP11B2</italic> gene where -344T serves as a reporter polymorphism and show that Hap-I leads to increased expression of h<italic>CYP11B2</italic>, with permissive effects on blood pressure and inflammatory milieu.</p> </sec> </abstract>