Hu Haitao, Hao Lanxiang, Tang Chunzhou, Zhu Yunxi, Jiang Qin, Yao Jin
The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China; Eye Hospital of Nanjing Medical University, Nanjing, China; Yancheng City No.1 People's Hospital, Yancheng, China.
Yancheng City No.1 People's Hospital, Yancheng, China.
Biochem Biophys Res Commun. 2018 Jan 15;495(3):2171-2177. doi: 10.1016/j.bbrc.2017.12.078. Epub 2017 Dec 15.
Ultra-violet (UV) radiation causes oxidative injuries to human retinal pigment epithelium (RPE) cells. We tested the potential effect of keratinocyte growth factor (KGF) against the process. KGF receptor (KGFR) is expressed in ARPE-19 cells and primary human RPE cells. Pre-treatment with KGF inhibited UV-induced reactive oxygen species (ROS) production and RPE cell death. KGF activated nuclear-factor-E2-related factor 2 (Nrf2) signaling in RPE cells, causing Nrf2 Ser-40 phosphorylation, stabilization and nuclear translocation as well as expression of Nrf2-dependent genes (HO1, NOQ1 and GCLC). Nrf2 knockdown (by targeted shRNAs) or S40T mutation almost reversed KGF-induced RPE cell protection against UV. Further studies demonstrated that KGF activated KGFR-Akt-mTORC1 signaling to mediate downstream Nrf2 activation. KGFR shRNA or Akt-mTORC1 inhibition not only blocked KGF-induced Nrf2 Ser-40 phosphorylation and activation, but also nullified KGF-mediated RPE cell protection against UV. We conclude that KGF-KGFR activates Akt-mTORC1 downstream Nrf2 signaling to protect RPE cells from UV radiation.
紫外线（UV）辐射会对人视网膜色素上皮（RPE）细胞造成氧化损伤。我们测试了角质形成细胞生长因子（KGF）对这一过程的潜在影响。KGF受体（KGFR）在ARPE-19细胞和原代人RPE细胞中表达。用KGF预处理可抑制紫外线诱导的活性氧（ROS）产生和RPE细胞死亡。KGF激活RPE细胞中的核因子E2相关因子2（Nrf2）信号通路，导致Nrf2丝氨酸40磷酸化、稳定和核转位以及Nrf2依赖性基因（HO1、NOQ1和GCLC）的表达。Nrf2敲低（通过靶向短发夹RNA）或S40T突变几乎逆转了KGF诱导的RPE细胞对紫外线的保护作用。进一步研究表明，KGF激活KGFR-Akt-mTORC1信号通路以介导下游Nrf2激活。KGFR短发夹RNA或Akt-mTORC1抑制不仅阻断了KGF诱导的Nrf2丝氨酸40磷酸化和激活，还消除了KGF介导的RPE细胞对紫外线的保护作用。我们得出结论，KGF-KGFR激活Akt-mTORC1下游的Nrf2信号通路，以保护RPE细胞免受紫外线辐射。
