Obstetrics and Gynecology Department, Changzhou Second People's Hospital, Changzhou, Jiangsu, China.
Obstetrics and Gynecology Department, Maternal and Child Health Care Hospital of Yancheng City, Yancheng, China.
Biochem Biophys Res Commun. 2018 Jun 18;501(1):178-185. doi: 10.1016/j.bbrc.2018.04.208. Epub 2018 May 5.
Oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) exposure to endometrial cells mimics ischemia-reperfusion injury. The present study tests the potential effect of keratinocyte growth factor (KGF) on the process. We show that KGF receptor KGFR is expressed in human endometrial T-HESC cells and primary murine endometrial cells. KGF pre-treatment protected endometrial cells from OGDR, inhibiting cell viability reduction and cell death. KGF attenuated OGDR-induced programmed necrosis in endometrial cells. Significantly, KGF activated Nrf2 signaling, causing Nrf2 Ser-40 phosphorylation, protein stabilization, nuclear translocation to promote anti-oxidant gene (HO1, NOQ1 and GCLC) expression. Nrf2 silencing (by targeted shRNAs) or CRISPR/Cas9 knockout almost abolished KGF-induced endometrial cell protection against OGDR. Furthermore, KGF activated Akt-mTOR signaling in endometrial cells. Whereas Akt-mTOR inhibitors (LY294002, AZD2014 and RAD001) abolished KGF-induced Nrf2 activation and anti-OGDR cytoprotection. Together, KGF protects endometrial cells from OGDR via activating Akt-mTOR-Nrf2 signaling.
氧和葡萄糖剥夺（OGD）-复氧（OGDR）暴露于子宫内膜细胞模拟缺血再灌注损伤。本研究测试角质细胞生长因子（KGF）对该过程的潜在影响。我们表明，角质细胞生长因子受体 KGFR 在人子宫内膜 T-HESC 细胞和原代小鼠子宫内膜细胞中表达。KGF 预处理可保护子宫内膜细胞免受 OGDR 损伤，抑制细胞活力降低和细胞死亡。KGF 减轻了 OGDR 诱导的子宫内膜细胞程序性坏死。重要的是，KGF 激活了 Nrf2 信号通路，导致 Nrf2 Ser-40 磷酸化、蛋白稳定、核易位，以促进抗氧化基因（HO1、NOQ1 和 GCLC）的表达。Nrf2 沉默（通过靶向 shRNAs）或 CRISPR/Cas9 敲除几乎消除了 KGF 诱导的对 OGDR 的子宫内膜细胞保护作用。此外，KGF 在子宫内膜细胞中激活了 Akt-mTOR 信号通路。然而，Akt-mTOR 抑制剂（LY294002、AZD2014 和 RAD001）消除了 KGF 诱导的 Nrf2 激活和抗 OGDR 细胞保护作用。总之，KGF 通过激活 Akt-mTOR-Nrf2 信号通路来保护子宫内膜细胞免受 OGDR 的影响。
