Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension

TLDR

Hypertension, a major cardiovascular risk factor, is shaped by lifelong environmental and genetic influences, and fetal stress has been shown to program disease development, a phenomenon that can be modeled in various animal studies. In maternal low‑protein diet rat models, early treatment with ACE inhibitors or angiotensin receptor antagonists prevents hypertension, implicating the renin‑angiotensin system. Early life upregulation of adrenal AT1b receptor expression, driven by promoter undermethylation, links fetal epigenetic changes to adult hypertension, suggesting similar mechanisms may underlie human disease.

Abstract

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT(1b) angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT(1b) gene in the adrenal is significantly undermethylated, and that in vitro, AT(1b) gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.