Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development

Abstract

Angiotensin type 1a receptor (AT1aR) is thought to play an important role in the development of hypertension. However, it is unknown how the AT1aR expression in vascular tissue is changed during the development of hypertension or if the degree of methylation in the AT1aR promoter correlates with the expression of AT1aR. To address these questions, we measured AT1aR mRNA, protein expression, and methylation status of the AT1aR promoter in the aorta and mesenteric artery of male spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rats acting as controls at pre-hypertensive (4 weeks), evolving (10 weeks), and established (20 weeks) stages of hypertension. The expression of the AT1aR mRNA and protein was not different between the SHRs and WKY rats at 4 weeks. However, they were significantly greater in SHRs than in WKY rats at 20 weeks. Bisulfite sequencing revealed that the AT1aR promoter from the aorta and mesenteric artery of the SHRs was progressively hypo-methylated with age as compared with their WKY rat counterparts. These results suggest that the heightened AT1aR expression in SHRs is related to the AT1aR promoter hypo-methylation, which might be a consequence of the increased blood pressure and may be important in the maintenance of high blood pressure.

Association of <b><i>AGTR1</i></b> Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

“…In a previous study, AGTR1 methylation levels were linked with age in rats [Pei et al, 2015]. However, the present study failed to demonstrate such an association between age and CpG methylation (data not shown), and ongoing research is required to investigate this.…”

“…Previous studies have shown that AGTR1 promoter hypomethylation is associated with the risk of primary hypertension in rats [Bogdarina et al, 2007[Bogdarina et al, , 2009[Bogdarina et al, , 2010Pei et al, 2015]. The present study hypothesized that an aberrant AGTR1 promoter methylation might also lead to EH in humans.…”

“…These results suggest that Agtr1b hypomethylation increases Agtr1b gene expression and eventually causes hypertension. In addition, Pei et al [2015] reported that elevated Agtr1a expression in spontaneously hypertensive rats is under a strong epigenetic influence by Agtr1a promoter hypomethylation, which may be important during the development of hypertension in rats. Consistent with previous studies, we observed a significantly lower level of CpG1 methylation in the AGTR1 promoter in EH cases than in controls.…”

“…In rodents, there are 2 distinct AGTR1 subtypes named Agtr1a and Agtr1b . Furthermore, several studies revealed that Agtr1a and Agtr1b hypomethylation in rat and mouse models are associated with heightened AGTR1 expression, which may be important in the development of hypertension [Bogdarina et al, 2007[Bogdarina et al, , 2009[Bogdarina et al, , 2010Pei et al, 2015]. However, the human genome only contains a single AGTR1 gene which is expressed in a pattern similar to that of the Agtr1a [Inagami, 1995], and the association between AGTR1 methylation and EH remains unclear in humans.…”

Epigenetic Regulation of Aldosterone Synthase Gene by Sodium and Angiotensin II

“…Pei et al22 reported hypomethylation of the promoter regions of the Ang II type 1a receptor gene in vascular tissues of hypertensive rats. Hypomethylation of the promoter regions of the Ang II type 1b receptor gene in the adrenal glands of the maternal low‐protein rat promoted hypertension through an exaggerated response to salt 23.…”