title: Gremlin inhibits UV-induced skin cell damages via activating VEGFR2-Nrf2 signaling.
abstract: 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.
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Jin-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Qiu-Yun
authors.initials: QY
authors.lastname: Xu
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Meng-Ting
authors.initials: MT
authors.lastname: Lin
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Yunnan Provincial Institute of Dermatology, Kunming 650032, Yunnan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Yunnan Provincial Institute of Dermatology, Kunming 650032, Yunnan, China.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Dermatology, BenQ Medical Center, Nanjing Medical University, Nanjing 210019, Jiangsu, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Bi
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Cheng
mesh_terms: D002478:Cells, Cultured; D019610:Cytoprotection; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000473:pathology* / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Nrf2; VEGFR2; gremlin; skin cell damage; ultra violet (UV)