Dexamethasone Promotes Hypertension By Allele-Specific Regulation Of The Human Angiotensinogen Gene [Gene Regulation]

January 7th, 2015 by Pandey, V. G., Jain, S., Rana, A., Puri, N., Arudra, S. K. C., Mopidevi, B., Kaw, M., Nasjletti, A., Kumar, A.

The human angiotensinogen gene (hAGT) gene has polymorphisms in its 2.5Kb promoter that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, -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 reduce cardiovascular risk. Hap -6A/-217A has increased promoter activity with enhanced transcription factor binding including, the glucocorticoid receptor (GR). Glucocorticoid therapy frequently causes hypertension, the mechanisms for which are incompletely understood. We have engineered double transgenic (TG) mice containing 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 consequential effects on the renin angiotensin system (RAS) and blood pressure. TG mice with Hap -6A and -6G were treated with and without low dose of a GR agonist, dexamethasone (DEX, 2.5μg/mL), for 72 hours. We find greater chromatin-GR binding with increased GR agonist-induced hAGT expression in liver and renal tissues of Hap -6A mice. Additionally, DEX treatment increased circulating hAGT and angiotensin II levels in Hap -6A mice, as compared to -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 RAS, and increased blood pressure and oxidative stress in Hap -6A mice.