Prenatal dexamethasone exposure induced pancreatic β-cell dysfunction and glucose intolerance of male offspring rats: Role of the epigenetic repression of ACE2
Prenatal dexamethasone exposure induced pancreatic β-cell dysfunction and glucose intolerance of male offspring rats: Role of the epigenetic repression of ACE2
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DOI：
10.1016/j.scitotenv.2022.154095
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发表时间：
2022-03-03
影响因子：
9.8
通讯作者：
Guo，Yu
中科院分区：
文献类型：
--
作者：
Dai，Yongguo;Kou，Hao;Guo，Yu
儿童和青少年糖尿病患病率呈逐渐上升趋势，这与发育过程中的不良环境，尤其是发育不良有关。目的探讨产前地塞米松暴露（PDE）对幼年仔鼠胰岛β细胞功能和葡萄糖稳态的影响。从妊娠第9天至第20天，对妊娠Wistar大鼠皮下注射地塞米松[0.1、0.2、0.4 mg/（kg.d）]。PDE损害的葡萄糖耐量在男性后代，而不是女性。在雄性后代中，PDE损害β细胞的发育和功能，伴随血管紧张素转换酶2（ACE 2）启动子区H3 K9 ac、H3 K14 ac和H3 K27 ac水平降低以及ACE 2表达抑制。同时，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3（HDAC 3）的表达。地塞米松在体外也能抑制ACE 2的表达和胰岛素的分泌。ACE 2的重组表达恢复了地塞米松抑制的胰岛素产生。此外，地塞米松还激活GR和HDAC 3，增加GR与HDAC 3的蛋白相互作用，促进GR-HDAC 3复合物与ACE 2启动子区的结合。RU 486和TSA都能消除地塞米松诱导的组蛋白乙酰化和ACE 2表达的下降。总之，ACE 2的抑制参与了PDE诱导的幼年雄性后代大鼠的β细胞功能障碍和葡萄糖耐受不良。
The prevalence of diabetes in children and adolescents has been rising gradually, which is relevant to adverse environment during development, especially prepartum. We aimed to explore the effects of prenatal dexamethasone exposure (PDE) on β-cell function and glucose homeostasis in juvenile offspring rats. Pregnant Wistar rats were subcutaneously administered with dexamethasone [0.1, 0.2, 0.4 mg/(kg.d)] from gestational day 9 to 20. PDE impaired glucose tolerance in the male offspring rather than the females. In male offspring, PDE impaired the development and function of β-cells, accompanied with lower H3K9ac, H3K14ac and H3K27ac levels in the promoter region of angiotensin-converting enzyme 2 (ACE2) as well as suppressed ACE2 expression. Meanwhile, PDE increased expression of glucocorticoid receptor (GR) and histone deacetylase 3 (HDAC3) in fetal pancreas. Dexamethasone also inhibited ACE2 expression and insulin productionin vitro. Recombinant expression of ACE2 restored insulin production inhibited by dexamethasone. In addition, dexamethasone activated GR and HDAC3, increased protein interaction of GR with HDAC3, and promoted the binding of GR-HDAC3 complex to ACE2 promoter region. Both RU486 and TSA abolished dexamethasone-induced decline of histone acetylation and ACE2 expression. In summary, suppression of ACE2 is involved in PDE induced β-cell dysfunction and glucose intolerance in juvenile male offspring rats.