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

Yanhong Wei; Junsong Gong; Takeshi Yoshida; Charles G. Eberhart; Zhenhua Xu; Ponvijay Kombairaju; Michael B. Sporn; James T. Handa; Elia J. Duh

doi:10.1016/j.freeradbiomed.2011.04.026

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

Yanhong Wei, Junsong Gong, Takeshi Yoshida, Charles G. Eberhart, Zhenhua Xu, Ponvijay Kombairaju, Michael B. Sporn, James T. Handa, Elia J. Duh

School of Medicine

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

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.

Original language	English (US)
Pages (from-to)	216-224
Number of pages	9
Journal	Free Radical Biology and Medicine
Volume	51
Issue number	1
DOIs	https://doi.org/10.1016/j.freeradbiomed.2011.04.026
State	Published - Jul 1 2011

Keywords

Apoptosis
Capillary degeneration
Cytokines
Inflammation
Ischemia-reperfusion
Knockout mice
Nuclear factor erythroid-2 related factor 2
Reactive oxygen species
Retina
Triterpenoids

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2011.04.026

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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.",

keywords = "Apoptosis, Capillary degeneration, Cytokines, Inflammation, Ischemia-reperfusion, Knockout mice, Nuclear factor erythroid-2 related factor 2, Reactive oxygen species, Retina, Triterpenoids",

author = "Yanhong Wei and Junsong Gong and Takeshi Yoshida and Eberhart, {Charles G.} and Zhenhua Xu and Ponvijay Kombairaju and Sporn, {Michael B.} and Handa, {James T.} and Duh, {Elia J.}",

note = "Funding Information: We are grateful to Shyam Biswal for sharing the Nrf2 −/− mice and thankful to Dr Masayuki Yamamoto who originally provided these mice to Shyam Biswal. We also thank Shyam Biswal and Rajesh Thimmulappa for many helpful suggestions during the study. The authors thank Timothy Kern, Jie Tang, and Yunpeng Du for invaluable technical assistance regarding the isolation of retinal vasculature and quantification of acellular capillaries and lucigenin assay for superoxide. We are grateful to Jiangxia Wang for providing advice about the data analysis, including ANOVA test. These studies were supported in part by research grants from the National Institutes of Health EY018138 (E.J.D.) and EY019904 (J.T.H.), the Juvenile Diabetes Research Foundation, Thome Foundation Grant, Robert Bond Welch Professorship, and Cindy and Jeong H. Kim, Ph.D. E.J.D. is a recipient of an RPB Career Development Award. ",

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doi = "10.1016/j.freeradbiomed.2011.04.026",

language = "English (US)",

volume = "51",

pages = "216--224",

journal = "Free Radical Biology and Medicine",

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T1 - Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury

AU - Wei, Yanhong

AU - Gong, Junsong

AU - Yoshida, Takeshi

AU - Eberhart, Charles G.

AU - Xu, Zhenhua

AU - Kombairaju, Ponvijay

AU - Sporn, Michael B.

AU - Handa, James T.

AU - Duh, Elia J.

N1 - Funding Information: We are grateful to Shyam Biswal for sharing the Nrf2 −/− mice and thankful to Dr Masayuki Yamamoto who originally provided these mice to Shyam Biswal. We also thank Shyam Biswal and Rajesh Thimmulappa for many helpful suggestions during the study. The authors thank Timothy Kern, Jie Tang, and Yunpeng Du for invaluable technical assistance regarding the isolation of retinal vasculature and quantification of acellular capillaries and lucigenin assay for superoxide. We are grateful to Jiangxia Wang for providing advice about the data analysis, including ANOVA test. These studies were supported in part by research grants from the National Institutes of Health EY018138 (E.J.D.) and EY019904 (J.T.H.), the Juvenile Diabetes Research Foundation, Thome Foundation Grant, Robert Bond Welch Professorship, and Cindy and Jeong H. Kim, Ph.D. E.J.D. is a recipient of an RPB Career Development Award.

PY - 2011/7/1

Y1 - 2011/7/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Capillary degeneration

KW - Cytokines

KW - Inflammation

KW - Ischemia-reperfusion

KW - Knockout mice

KW - Nuclear factor erythroid-2 related factor 2

KW - Reactive oxygen species

KW - Retina

KW - Triterpenoids

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

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