Epigenetic repression of AT2 receptor is involved in β cell dysfunction and glucose intolerance of adult female offspring rats exposed to dexamethasone prenatally
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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AT2 受体的表观遗传抑制与产前暴露于地塞米松的成年雌性子代大鼠的 β 细胞功能障碍和葡萄糖耐受不良有关
DOI：
10.1016/j.taap.2020.115187
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发表时间：
2020-10-01
影响因子：
3.8
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Kou, Hao;Gui, Shuxia;Wang, Hui
产前暴露于地塞米松（PDE）损害胰腺β细胞发育和葡萄糖稳态的后代，特别是女性。为了探索潜在的宫内编程机制，妊娠Wistar大鼠皮下注射地塞米松（0，0.2和0.8 mg/kg.d），从妊娠第9天（GD）至20。分别在GD 20（胎仔）和出生后第28周（成年）采集雌性后代。PDE降低了胎儿和成人的血清胰岛素水平、β细胞质量和胰腺胰岛素表达，导致成熟后的葡萄糖耐受不良。PDE雌性大鼠出生前后胰腺血管紧张素II受体2型（AT 2 R）表达持续受到抑制，伴随AT 2 R启动子区组蛋白3赖氨酸14乙酰化（H3 K14 ac）和H3 K27 ac水平降低。PDE可增加胎儿胰腺糖皮质激素受体（GR）和组蛋白去乙酰化酶2（HDAC 2）的基因表达。地塞米松可抑制INS-1细胞胰岛素合成，同时激活GR和HDAC 2的表达。地塞米松抑制AT 2 R的表达，但仅降低AT 2 R启动子中的H3 K27 ac水平。地塞米松可增强GR与HDAC 2蛋白的相互作用以及GR/HDAC 2复合物与AT 2 R启动子的结合。此外，AT 2 R的过表达可以恢复地塞米松诱导的胰岛素生物合成的抑制，GR拮抗剂和组蛋白去乙酰化酶都可以消除降低的H3 K27 ac水平和AT 2 R基因表达。总之，出生前后AT 2 R的持续表观遗传抑制可能与PDE成年雌性后代的β细胞功能障碍和葡萄糖耐受不良有关。
Prenatal exposure to dexamethasone (PDE) impairs pancreatic beta 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, beta 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 beta cell dysfunction and glucose intolerance of the PDE adult female offspring.