Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death

J Neurochem. 2013 Dec;127(5):669-80. doi: 10.1111/jnc.12325. Epub 2013 Jun 17.


NF-E2 related factor 2 (Nrf2) is a key transcription factor that plays a pivotal role in endogenous protection against oxidative stress. However, the role of Nrf2 in visual disorders remains unclear. It has been reported that oxidative stress is thought of as one of the causes of glaucoma. Here, we investigate whether the function of Nrf2 in oxidative stress-induced retinal ganglion cell (RGC) death. This study used adult male Nrf2 deficient mice (Nrf2 KO) and age- and sex-matched wild-type (WT) mice. We dissociated and purified N-4-[4-didecylaminostryryl]-N-methyl-pyridinium iodide-labeled RGCs with fluorescence-activated cell sorting, and tried to detect the Nrf2 and Keap1 genes. In the absence of nerve crush (NC), the number of RGCs in Nrf2 KO mice was almost same as that in WT mice. 1-(2-cyano-3-, 12-dioxooleana-1, 9 (11)-dien-28-oyl) imidazole (CDDO-Im), an Nrf2 activator, prevented NC-induced loss of RGCs in WT mice. Seven days after NC, without treatment, the number of RGCs in Nrf2 KO mice was significantly lower than in WT mice. In addition, after CDDO-Im treatment, quantitative RT-PCR showed increased expression of antioxidant and phase II detoxifying enzymes. These results suggest that up-regulation of Nrf2 signaling after CDDO-Im treatment may be a novel therapeutic strategy for the protection of RGCs, especially in glaucoma. This study suggests that NF-E2 related factor 2 (Nrf2), a transcription factor, plays a pivotal role in counteracting oxidative stress. Most importantly, a neuroprotective effect against oxidative stress-induced retinal ganglion cell (RGC) death was achieved with the pharmacological Nrf2 activator CDDO-Im. This suggests that pharmacological treatment to up-regulate Nrf2 signaling may be a new therapeutic technique to protect RGCs.

Keywords: Nrf2; glaucoma; neuroprotection; oxidative stress; retinal ganglion cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cell Nucleus / metabolism
  • Female
  • Glaucoma / drug therapy
  • Glaucoma / metabolism*
  • Glaucoma / pathology
  • Imidazoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neuroprotective Agents / pharmacology
  • Oleanolic Acid / analogs & derivatives
  • Oleanolic Acid / pharmacology
  • Oxidative Stress / physiology*
  • RNA, Messenger / metabolism
  • Retinal Ganglion Cells / metabolism*
  • Retinal Ganglion Cells / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • Antioxidants
  • Imidazoles
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Oleanolic Acid