Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension.

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (e.g. 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 modelled 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 (RAS) in this process. Here we show that in this model, expression of the AT1b 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 AT1b gene in the adrenal is significantly undermethylated, and that in vitro, AT1b 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.

高血压是心血管和脑血管疾病的主要危险因素。终生的环境因素（如盐摄入、肥胖、饮酒）和遗传因素显然对高血压的发展有促进作用，但也已确定子宫内的应激可能会“规划”该疾病日后的发展。这种被称为胎儿编程的现象可以在一系列实验动物模型中进行模拟。在母体低蛋白饮食的编程大鼠模型中，在生命早期给予血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂可以预防高血压的发展，因此表明肾素 - 血管紧张素系统（RAS）参与了这一过程。在此我们表明，在该模型中，肾上腺中AT1b血管紧张素受体基因的表达在出生后第一周就上调，导致受体蛋白表达增加，这与其他人观察到的肾上腺血管紧张素反应性增加是一致的。此外，我们表明肾上腺中AT1b基因的近端启动子甲基化程度显著降低，并且在体外，AT1b基因表达高度依赖于启动子甲基化。这些数据表明胎儿所受的损伤与基因的表观遗传修饰之间存在联系，以及由此导致的成年期基因表达的改变，最终导致高血压的发展。人类高血压的发展似乎很可能涉及类似的影响。