Maternal malnutrition-induced epigenetic alteration linked to offspring hypertension
Maternal diet has profound, long-lasting effects on offspring. For example, maternal malnutrition results in fetal exposure to excessive glucocorticoid, which can result in metabolic reprogramming and hypertension. In this episode, Toshiro Fujita and colleagues exposed pregnant rodents to a low-protein diet or to the synthetic glucocorticoid dexamethasone and demonstrated that the offspring of these dams were prone to salt-sensitive hypertension. In utero glucocorticoid exposure resulted in aberrant DNA methylation of hypothalamic angiotensin receptor type 1a, resulting in increased expression. Moreover, mice lacking the DNA methyltransferase 3a became hypertensive in the absence of glucocorticoid exposure, while animals lacking the angiotensin receptor were protected from prenatal glucocorticoid exposure-induced hypertension. Together, these results reveal epigenetic modulation of angiotensin signaling underlies development of hypertension that results from prenatal exposure to glucocorticoids.
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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.
Authors
Fumiko Kawakami-Mori, Mitsuhiro Nishimoto, Latapati Reheman, Wakako Kawarazaki, Nobuhiro Ayuzawa, Kohei Ueda, Daigoro Hirohama, Daisuke Kohno, Shigeyoshi Oba, Tatsuo Shimosawa, Takeshi Marumo, Toshiro Fujita
