Abstract
Single nucleotide polymorphisms (SNPs) in the human angiotensinogen (hAGT) gene may modulate its transcription and affect the regulation of blood pressure via activation of the renin-angiotensin aldosterone system (RAAS). In this regard, we have identified polymorphisms in the 2.5 Kb promoter of the hAGT gene that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C & -1178G/A). hAGT gene with Hap -6A/-217A (Hap I) is associated with increased blood pressure whereas, Hap -6G/-217G (Hap II) is associated with normal blood pressure in human subjects. Since RAAS over activity contributes to hypertension in obesity, we have made transgenic mice (TG) containing either Hap I or Hap II of the hAGT gene to understand the role of obesity on its transcriptional regulation. Although, a high-fat diet (60% Kcal from fat, 12 weeks) elevates hAGT and mAGT regardless of haplotype, this effect is significantly (p<0.05) accentuated in Hap I mice, in both adipose and liver tissues. Chromatin Immuno- precipitation (ChIP) assay shows an increased binding of transcription factors including, GR, CEBPβ and STAT3 to the chromatin of the Hap I TG mice after high-fat diet as compared to Hap II TG mice (p<0.05). Differential plasma levels of hAGT in Hap II and I mice, after high-fat diet, further corroborate the variable transcriptional regulation of the hAGT, governed by gene-haplotypes. Taken together, our results show that SNPs in the Hap-I of the hAGT gene promote high-fat diet-induced binding of transcription factors GR, CEBP-β and STAT3, which lead to elevated expression of the hAGT gene in hepatic and adipose tissues.
Highlights
Hypertension is a complex disorder arising from intricate crosstalk between environmental factors and genetic predispositions [1, 2]
We measured the expression of CEBPβ, STAT3 and GR in adipose and liver of adult male Hap I and Hap II transgenic mice (TG) mice after high fat diet by Q-RT-PCR
Since single nucleotide polymorphism (SNPs) at the nucleotide position, -217 and -1561/-1562 in the Hap I TG mice have stronger homology with the consensus binding sites of GR, STAT3 and C/EBPβ; we examined the effect of the high-fat diet (HFD) on the binding of these transcription factors to the -217 and -1561/-1562 regions of the human angiotensinogen (hAGT) gene promoter
Summary
Hypertension is a complex disorder arising from intricate crosstalk between environmental factors and genetic predispositions [1, 2]. Obesity and hypertension frequently co-existent, every obese individual is not hypertensive [3, 4]. In this regard, we have focused our work on groups of single nucleotide polymorphism (SNPs) in genes relevant to the regulation of mammalian blood pressure. Human angiotensinogen (hAGT) gene is associated with hypertension, its transcriptional regulation in pathological scenarios like obesity is poorly understood. The role of AGT gene in hypertension is suggested by studies that showed elevated plasma AGT level by increasing AGT genecopy number and an increase in blood pressure in TG mice [12, 13]. We have used TG-mice containing different haplotypes of the hAGT gene to understand the effect of different SNPs on transcriptional regulation and blood pressure regulation in an in vivo setting
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