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Tytuł:
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Epigenetic repression of AT2 receptor is involved in β cell dysfunction and glucose intolerance of adult female offspring rats exposed to dexamethasone prenatally.
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Autorzy:
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Kou H; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 40071, China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China.
Gui S; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Dai Y; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Guo Y; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China. Electronic address: .
Wang H; Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China. Electronic address: .
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Źródło:
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Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2020 Oct 01; Vol. 404, pp. 115187. Date of Electronic Publication: 2020 Aug 11.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: New York, NY : Academic Press
Original Publication: New York.
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MeSH Terms:
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Glucose Intolerance*
Prenatal Exposure Delayed Effects*
Dexamethasone/*toxicity
Insulin-Secreting Cells/*metabolism
Receptor, Angiotensin, Type 2/*metabolism
Animals ; Epigenesis, Genetic ; Female ; Gene Expression Regulation/drug effects ; Glucocorticoids/toxicity ; Pregnancy ; Rats ; Receptor, Angiotensin, Type 2/genetics
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Contributed Indexing:
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Keywords: Angiotensin Receptor II; Dexamethasone; Glucose Intolerance; Histone Acetylation; Pancreatic β Cell
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Substance Nomenclature:
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0 (Glucocorticoids)
0 (Receptor, Angiotensin, Type 2)
7S5I7G3JQL (Dexamethasone)
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Entry Date(s):
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Date Created: 20200814 Date Completed: 20210106 Latest Revision: 20210106
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Update Code:
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20240105
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DOI:
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10.1016/j.taap.2020.115187
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PMID:
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32791177
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Prenatal exposure to dexamethasone (PDE) impairs pancreatic β cell development and glucose homeostasis in offspring especially females. To explore the underlying intrauterine programming mechanism, pregnant Wistar rats were subcutaneously administered with dexamethasone (0, 0.2 and 0.8 mg/kg·d) from gestational days (GD) 9 to 20. Female offspring were collected on GD20 (fetus) and in postnatal week 28 (adult), respectively. PDE reduced the serum insulin levels, β cell mass, and pancreatic insulin expressions in fetuses and adults, causing glucose intolerance after maturity. The persistent suppression of pancreatic angiotensin II receptor type 2 (AT2R) expression before and after birth could be observed in the PDE females, which is accompanied with decreased histone 3 lysine 14 acetylation (H3K14ac) and H3K27ac levels in AT2R promoter. PDE increased the gene expressions of glucocorticoid receptor (GR) and histone deacetylase 2 (HDAC2) in fetal pancreas. Furthermore, dexamethasone inhibited insulin biosynthesis while activated GR and HDAC2 expression in the rat INS-1 cells. The AT2R expression was repressed by dexamethasone in vitro but only H3K27ac levels in AT2R promoter were lowered. Dexamethasone enhanced the interaction between GR and HDAC2 proteins as well as the binding of GR/HDAC2 complex to AT2R promoter. Moreover, overexpression of AT2R could restore the suppressed insulin biosynthesis induced by dexamethasone in vitro, and both GR antagonist and histone deacetylase abolished the decreased H3K27ac level and gene expression of AT2R. In conclusion, continuous epigenetic repression of AT2R before and after birth may be involved in β cell dysfunction and glucose intolerance of the PDE adult female offspring.
Competing Interests: Declaration of Competing Interest All authors declare they have no conflict of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
