title: Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Junsong
authors.initials: J
authors.lastname: Gong
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.forename: Ponvijay
authors.initials: P
authors.lastname: Kombairaju
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
mesh_terms: D000818:Animals; D000975:Antioxidants; D002196:Capillaries / Q000473:pathology*; D019610:Cytoprotection; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C445068:bardoxolone methyl