title: Dexamethasone promotes hypertension by allele-specific regulation of the human angiotensinogen gene.
abstract: The human angiotensinogen (hAGT) gene has polymorphisms in its 2.5-kb promoter that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, and -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C, and -1178G/A). Hap -6A/-217A is associated with human hypertension, whereas Hap -6G/-217G reduces cardiovascular risk. Hap -6A/-217A has increased promoter activity with enhanced transcription factor binding, including to the glucocorticoid receptor (GR). Glucocorticoid therapy frequently causes hypertension, the mechanisms for which are incompletely understood. We have engineered double transgenic (TG) mice containing the human renin gene with either Hap of the hAGT gene and examined the physiological significance of glucocorticoid-mediated allele-specific regulation of the hAGT gene. We have also studied the consequential effects on the renin angiotensin system and blood pressure. TG mice with Hap -6A and -6G were treated with and without a low dose of a GR agonist, dexamethasone (2.5 μg/ml), for 72 h. We found greater chromatin-GR binding with increased GR agonist-induced hAGT expression in liver and renal tissues of Hap -6A mice. Additionally, dexamethasone treatment increased circulating hAGT and angiotensin II levels in Hap -6A mice, as compared with -6G mice. Importantly, GR agonist significantly increased blood pressure and redox markers in TG mice with Hap-6A of the hAGT gene. Taken together, our results show, for the first time, that glucocorticoids affect hAGT expression in a haplotype-dependent fashion with SNPs in Hap -6A favoring agonist-induced GR binding. This leads to increased expression of the hAGT, up-regulation of the renin angiotensin system, and increased blood pressure and oxidative stress in Hap -6A mice.
authors.affiliation: From the Departments of Physiology and Pharmacology and the Department of Pharmacology, New York Medical College, Valhalla, New York, 10595.
authors.forename: Varunkumar G
authors.initials: VG
authors.lastname: Pandey
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Jain
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Anita
authors.initials: A
authors.lastname: Rana
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.affiliation: Pathology, College of Medicine, University of Toledo, Toledo, Ohio 43614 and.
authors.forename: Sri Krishna C
authors.initials: SK
authors.lastname: Arudra
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Brahmaraju
authors.initials: B
authors.lastname: Mopidevi
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Kaw
authors.affiliation: From the Departments of Physiology and Pharmacology and.
authors.forename: Alberto
authors.initials: A
authors.lastname: Nasjletti
authors.affiliation: From the Departments of Physiology and Pharmacology and ashok.kumar2@utoledo.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000483:Alleles; D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D015151:Immunoblotting; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C000606290:SOD1 protein, human; D000808:Angiotensinogen; D000804:Angiotensin II; D003907:Dexamethasone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Angiotensin II; Angiotensinogen; Genetic Polymorphism; Renin Angiotensin System; Single-nucleotide Polymorphism (SNP); Transgenic Mice