Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta.
Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta.
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Nrf2信号和自噬参与糖尿病引起的小鼠胎盘发育缺陷
DOI：
10.1098/rsob.160064
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发表时间：
2016-07
期刊：
影响因子：
5.8
通讯作者：
Liu GS
中科院分区：
文献类型：
--
作者：
He MY;Wang G;Han SS;Jin Y;Li H;Wu X;Ma ZL;Cheng X;Tang X;Yang X;Liu GS
糖尿病损害胎盘发育已被广泛接受，但糖尿病损害胎盘发育的机制仍存在争议。本研究证明，妊娠前糖尿病（PGDM）诱导的小鼠胎盘发育缺陷主要表现为胎盘形态结构的改变。滋养层细胞中分化相关基因表达的改变而不是细胞增殖/凋亡是导致小鼠胎盘中发现的表型的原因。同时，在PGDM小鼠胎盘中观察到过量的活性氧（ROS）产生和活化的核因子红细胞2相关因子2（Nrf 2）信号传导。使用BeWo细胞，我们还证明了在以高浓度葡萄糖为特征的环境中产生过量的ROS并且Nrf 2信号传导分子被激活。更有趣的是，当通过抑制Nrf 2-wt或Nrf 2-shRNA操纵内源性Nrf 2表达时，滋养层细胞中分化相关基因的表达发生了改变。此外，PGDM干扰小鼠胎盘和BeWo细胞中的自噬，这意味着自噬也直接或间接参与PGDM诱导的胎盘表型。因此，我们揭示了功能失调的氧化应激激活的Nrf 2信号传导和自噬可能是PGDM诱导的小鼠胎盘发育缺陷的原因。其机制可能是通过干扰滋养细胞分化相关基因的表达。
It is widely accepted that diabetes mellitus impairs placental development, but the mechanism by which the disease operates to impair development remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in placental development in mice are mainly characterized by the changes of morphological structure of placenta. The alteration of differentiation-related gene expressions in trophoblast cells rather than cell proliferation/apoptosis is responsible for the phenotypes found in mouse placenta. Meanwhile, excess reactive oxygen species (ROS) production and activated nuclear factor erythroid2-related factor 2 (Nrf2) signalling were observed in the placenta of mice suffering from PGDM. Using BeWo cells, we also demonstrated that excess ROS was produced and Nrf2 signalling molecules were activated in settings characterized by a high concentration of glucose. More interestingly, differentiation-related gene expressions in trophoblast cells were altered when endogenous Nrf2 expression is manipulated by transfecting Nrf2-wt or Nrf2-shRNA. In addition, PGDM interferes with autophagy in both mouse placenta and BeWo cells, implying that autophagy is also involved, directly or indirectly, in PGDM-induced placental phenotypes. Therefore, we revealed that dysfunctional oxidative stress-activated Nrf2 signalling and autophagy are probably responsible for PGDM-induced defects in the placental development of mice. The mechanism was through the interference with differentiation-related gene expression in trophoblast cells.