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Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension
Fumiko Kawakami-Mori, … , Takeshi Marumo, Toshiro Fujita
Fumiko Kawakami-Mori, … , Takeshi Marumo, Toshiro Fujita
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e95625. https://doi.org/10.1172/jci.insight.95625.
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Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension

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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

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Figure 1

Comparison between offspring treated with a low-protein diet (LP) and those treated with dexamethasone (Dex).

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Comparison between offspring treated with a low-protein diet (LP) and th...
(A) Real-time PCR of Hsd11b2 mRNA expression (normalized against Actb) in placenta at the end of the third trimester (F19–20) of pregnant rats receiving a normal-protein diet (NP) (n = 13) or a low-protein diet (LP) (n = 14). Filled circles, NP-treated rats; open circles, LP-treated rats. (B) Body weight (BW) at weeks 1 (n = 16) and 12 (n = 7) in male NP- and LP-treated offspring. (C) BW at weeks 1 and 12 in Dex-untreated (control) (n = 16 and 12) and Dex-treated (n = 20 and 8, respectively) offspring. Filled circles, control offspring; open circles, Dex-treated offspring. (D) Systolic BP measured by radiotelemetry in NP-treated and LP-treated offspring that received a 0.5% salt (NS) or 8% salt (HS) diet for 1 week (n = 4) (left panel). Mean arterial pressure by radiotelemetry before and after 1 week of HS in NP-treated and LP-treated offspring (right panel). Filled circles, NP group; open circles, LP group. (E) Systolic BP, measured by radiotelemetry, in control and Dex-treated offspring that received 0.5% salt (NS) or 8% salt (HS) diet for 1 week (n = 4) (left panel). Mean arterial pressure, measured by radiotelemetry, before and after 1 week of HS in control and Dex-treated offspring (right panel). Filled circles, control offspring; open circles, Dex-treated offspring. Throughout, data represent means ± SEM. In A, B, and C, *P < 0.05 versus NP offspring or control offspring (t test). In D, *P < 0.05 in NP-treated group versus LP-treated group and in NS versus HS within each group. In E, *P < 0.05 in control versus Dex-treated offspring and in NS versus HS within each group (2-way repeated ANOVA, Bonferroni post hoc test).

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