Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia–reperfusion injury

• Published in: Free radical biology & medicine 2011-07, Vol.51 (1), p.216-224
• Main Authors: Wei, Yanhong, Gong, Junsong, Yoshida, Takeshi, Eberhart, Charles G., Xu, Zhenhua, Kombairaju, Ponvijay, Sporn, Michael B., Handa, James T., Duh, Elia J.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Apoptosis; Capillaries - pathology; Capillary degeneration; Cytokines; Cytoprotection; ganglia; gene expression; Gene Expression - drug effects; histopathology; Inflammation; Ischemia–reperfusion; Knockout mice; leukocytes; macular degeneration; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic - metabolism; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nuclear factor erythroid-2 related factor 2; Oleanolic Acid - administration & dosage; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Retina; Retinal Vessels - pathology; Triterpenoids
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.04.026

Retinal ischemia–reperfusion (I/R) involves an extensive increase in reactive oxygen species as well as proinflammatory changes that result in significant histopathologic damage, including neuronal and vascular degeneration. Nrf2 has a well-known cytoprotective role in many tissues, but its protective function in the retina is unclear. We investigated the possible role of Nrf2 as a protective mechanism in retinal ischemia–reperfusion injury using Nrf2−/− mice. I/R resulted in an increase in retinal levels of superoxide and proinflammatory mediators, as well as leukocyte infiltration of the retina and vitreous, in Nrf2+/+ mice. These effects were greatly accentuated in Nrf2−/− mice. With regard to histopathologic damage, Nrf2−/− mice exhibited loss of cells in the ganglion cell layer and markedly accentuated retinal capillary degeneration, as compared to wild-type. Treatment with the Nrf2 activator CDDO-Me increased antioxidant gene expression and normalized I/R-induced superoxide in the retina in wild-type but not Nrf2−/− mice. CDDO-Me treatment abrogated retinal capillary degeneration induced by I/R in wild-type but not Nrf2−/− mice. These studies indicate that Nrf2 is an important cytoprotective mechanism in the retina in response to ischemia–reperfusion injury and suggest that pharmacologic induction of Nrf2 could be a new therapeutic strategy for retinal ischemia–reperfusion and other retinal diseases.