Gremlin inhibits UV-induced skin cell damages via activating VEGFR2-Nrf2 signaling
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Chao Ji1,*, Jin-wen Huang1,*, Qiu-yun Xu1, Jing Zhang1, Meng-ting Lin1, Ying Tu2, Li He2, Zhi-gang Bi3, Bo Cheng1
1Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
2Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Yunnan Provincial Institute of Dermatology, Kunming 650032, Yunnan, China
3Department of Dermatology, BenQ Medical Center, Nanjing Medical University, Nanjing 210019, Jiangsu, China
*These authors have contributed equally to this work
Bo Cheng, email: [email protected]
Zhi-Gang Bi, email: [email protected]
Keywords: ultra violet (UV), skin cell damage, gremlin, VEGFR2, Nrf2
Received: September 13, 2016 Accepted: September 23, 2016 Published: October 04, 2016
Ultra Violet (UV) radiation induces reactive oxygen species (ROS) production, DNA oxidation and single strand breaks (SSBs), which will eventually lead to skin cell damages or even skin cancer. Here, we tested the potential activity of gremlin, a novel vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) agonist, against UV-induced skin cell damages. We show that gremlin activated VEGFR2 and significantly inhibited UV-induced death and apoptosis of skin keratinocytes and fibroblasts. Pharmacological inhibition or shRNA-mediated knockdown of VEGFR2 almost abolished gremlin-mediated cytoprotection against UV in the skin cells. Further studies showed that gremlin activated VEGFR2 downstream NF-E2-related factor 2 (Nrf2) signaling, which appeared required for subsequent skin cell protection. Nrf2 shRNA knockdown or S40T dominant negative mutation largely inhibited gremlin-mediated skin cell protection against UV. At last, we show that gremlin dramatically inhibited UV-induced ROS production and DNA SSB formation in skin keratinocytes and fibroblasts. We conclude that gremlin protects skin cells from UV damages via activating VEGFR2-Nrf2 signaling. Gremlin could be further tested as a novel anti-UV skin protectant.
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