Gremlin inhibits UV-induced skin cell damages via activating VEGFR2-Nrf2 signaling

Oncotarget. 2016 Dec 20;7(51):84748-84757. doi: 10.18632/oncotarget.12454.


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.

Keywords: Nrf2; VEGFR2; gremlin; skin cell damage; ultra violet (UV).

MeSH terms

  • Cells, Cultured
  • Cytoprotection
  • DNA Breaks, Single-Stranded
  • DNA Damage
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • NF-E2-Related Factor 2 / metabolism
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Skin / pathology*
  • Skin / radiation effects
  • Ultraviolet Rays / adverse effects
  • Vascular Endothelial Growth Factor Receptor-2 / agonists
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • GREM1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2