Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet.
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.
['Hu|Haitao|H|', 'Hao|Lanxiang|L|', 'Tang|Chunzhou|C|', 'Zhu|Yunxi|Y|', 'Jiang|Qin|Q|', 'Yao|Jin|J|']
D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D051523:Fibroblast Growth Factor 7 D006801:Humans D051267:NF-E2-Related Factor 2 D051058:Oncogene Protein v-akt D011829:Radiation Dosage D051497:Receptor, Fibroblast Growth Factor, Type 2 D055213:Retinal Pigment Epithelium D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D016896:Treatment Outcome D014466:Ultraviolet Rays
Ultra-violet (UV) Retinal pigment epithelium (RPE) cells Keratinocyte growth factor (KGF) Nrf2 Akt-mTORC1