RRC ID 54530
Author Kawakami-Mori F, Nishimoto M, Reheman L, Kawarazaki W, Ayuzawa N, Ueda K, Hirohama D, Kohno D, Oba S, Shimosawa T, Marumo T, Fujita T.
Title Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension.
Journal JCI Insight
Abstract Maternal malnutrition, which causes prenatal exposure to excessive glucocorticoid, induces adverse metabolic programming, leading to hypertension in offspring. In offspring of pregnant rats receiving a low-protein diet or dexamethasone, a synthetic glucocorticoid, mRNA expression of angiotensin receptor type 1a (Agtr1a) in the paraventricular nucleus (PVN) of the hypothalamus was upregulated, concurrent with reduced expression of DNA methyltransferase 3a (Dnmt3a), reduced binding of DNMT3a to the Agtr1a gene, and DNA demethylation. Salt loading increased BP in both types of offspring, suggesting that elevated hypothalamic Agtr1a expression is epigenetically modulated by excessive glucocorticoid and leads to adult-onset salt-sensitive hypertension. Consistent with this, dexamethasone treatment of PVN cells upregulated Agtr1a, while downregulating Dnmt3a, and decreased DNMT3a binding and DNA demethylation at the Agtr1a locus. In addition, Dnmt3a knockdown upregulated Agtr1a independently of dexamethasone. Hypothalamic neuron-specific Dnmt3a-deficient mice exhibited upregulation of Agtr1a in the PVN and salt-induced BP elevation without dexamethasone treatment. By contrast, dexamethasone-treated Agtr1a-deficient mice failed to show salt-induced BP elevation, despite reduced expression of Dnmt3a. Thus, epigenetic modulation of hypothalamic angiotensin signaling contributes to salt-sensitive hypertension induced by prenatal glucocorticoid excess in offspring of mothers that are malnourished during pregnancy.
Volume 3(21)
Published 2018-11-2
DOI 10.1172/jci.insight.95625
PII 95625
PMID 30385711
PMC PMC6238751
MeSH Animals Animals, Newborn DNA (Cytosine-5-)-Methyltransferases / metabolism DNA Methylation / genetics* DNA Methyltransferase 3A Dexamethasone / supply & distribution Epigenomics Female Glucocorticoids / supply & distribution Hypertension / genetics* Hypertension / metabolism Male Mice Paraventricular Hypothalamic Nucleus / metabolism* Pregnancy Prenatal Exposure Delayed Effects Protein-Energy Malnutrition / complications RNA, Messenger / genetics Rats Rats, Sprague-Dawley Receptor, Angiotensin, Type 1 / metabolism* Up-Regulation / physiology
IF 6.205
Times Cited 7
Mice RBRC04696