The role of the Nrf2-mediated defense system in corneal epithelial wound healing

Free Radic Biol Med. 2013 Aug;61:333-42. doi: 10.1016/j.freeradbiomed.2013.04.008. Epub 2013 Apr 12.


The corneal epithelium exists at the surface of cornea and is easily damaged by external stresses such as UV radiation or physical injury. The Nrf2-mediated defense system plays a central role in protecting cells by activating genes against these types of stress. In this study, we investigated the role of the Nrf2-mediated defense system in corneal epithelial wound healing by using Nrf2-knockout (KO) mice. Nrf2 was expressed in the corneal epithelium of wild-type (WT) mice, but not in KO mice. Observation of wounds after 24h of healing revealed that healing of the corneal epithelium was significantly delayed in the Nrf2 KO mice, whereas Nrf2 was activated in the corneal epithelium of WT mice. Ki-67 staining revealed that the number of Ki-67-positive proliferating cells was significantly lower in the Nrf2 KO mice than in the WT mice at 24-36h after injury; however, these numbers were approximately equivalent by 48h. To clarify the role of Nrf2 during wound healing, we performed in vitro experiments with siRNA for Nrf2 and its suppressor Keap1. Nrf2 knockdown significantly delayed corneal epithelial cell migration, but did not affect cell proliferation. Conversely, Keap1 knockdown significantly accelerated cell migration. These results suggest that Nrf2 contributed to the corneal epithelial wound-healing process by accelerating cell migration, and Nrf2 would therefore be a good target for the treatment of corneal epithelial diseases such as dry eye or chronic corneal epithelial defect.

Keywords: Cell migration; Cell proliferation; Corneal epithelium; Free radicals; Keap1; Nrf2; Wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Cell Movement
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology
  • Epithelial Cells / physiology
  • Epithelium, Corneal / physiology*
  • Kelch-Like ECH-Associated Protein 1
  • Ki-67 Antigen / analysis
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / physiology*
  • Wound Healing*


  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Ki-67 Antigen
  • Mki67 protein, mouse
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse