Abstract P279: Human Angiotensin Receptor Gene Variations, Hypertension & Reno-Vascular Complications

Abstract

Angiotensin receptor type 1 (AT1R), a G-protein coupled receptor mediates the effect of angiotensin-II and contributes to the pathophysiological consequences of reno-vascular system. AT1R-signaling promotes renal sodium retention, vascular remodeling, hypertension, and end organ damage. Genetic variations that increase AT1R can cause pathological outcomes associated with renin angiotensin system overactivity. However, genetically variable, transcriptional regulation of the human AT1R gene is poorly understood. In this regard, the human AT1R gene has a haplotype block of four SNPs: T/A at -810, T/G at -713, A/C at -214, and A/G at -153 in its promoter. Variants -810T, -713T, -214A, and -153A always occur together (named haplotype-I or Hap-I) and variants -810A, -713G, -214C, and -153G always occur together (haplotype-II or Hap-II). We have found that hap-I is associated with hypertension in Caucasians. Thus, we generated transgenic (TG) mice with hap-II and I of the hAT1R gene to study its transcriptional regulation in vivo . TG mice with hap-I have higher baseline expression of hAT1R (3.9 folds) in the kidney with increased blood pressure (Hap-I, 126±3 vs. Hap II, 115±4). Since, diet-induced obesity is accompanied by systemic inflammation and redox imbalance that, in turn, alter the cellular transcriptional milieu, we gave Western diet (WD) treatment to our TG mice. Preliminary studies show that transcription factors like USF1, GR and STAT3 binds strongly (2.1; 2.3; 1.7 folds respectively Vs Hap-II) to increase hAT1R expression (5.8 folds) and resulting blood pressure (136±2 vs. 120±3 in Hap II) in TG-mice with hap-I, as compared to hap-II. Complementary experiments show increased inflammatory and redox markers in renal tissues of Hap-I mice, when compared to Hap-II, after WD; including, IL6 (5.9 fold), NOX1 (5.2 fold), CRP (9.8 fold), and TNFα (6.3 fold). Also, histochemical analysis of kidneys show an elevated pathology in Hap-I TG mice. Thus, haplotype-dependent transcriptional regulation of the hAT1R gene causes increased hAT1R expression and blood pressure, in Hap-I TG mice. Importantly, WD exacerbates this differential gene- expression regulation, further increasing hAT1R and promoting a pro-oxidant/inflammatory milieu in mice with Hap-I.