TY - JOUR
T1 - Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension
AU - Bogdarina, Irina
AU - Welham, Simon
AU - King, Peter J.
AU - Burns, Shamus P.
AU - Clark, Adrian J.L.
PY - 2007/3/2
Y1 - 2007/3/2
N2 - 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 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.
AB - 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 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.
KW - Angiotensin receptors
KW - DNA methylation
KW - Fetal programming
KW - Hypertension
UR - http://www.scopus.com/inward/record.url?scp=33947517327&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000258855.60637.58
DO - 10.1161/01.RES.0000258855.60637.58
M3 - Article
C2 - 17255528
AN - SCOPUS:33947517327
VL - 100
SP - 520
EP - 526
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 4
ER -