NRF2 plays a protective role in diabetic retinopathy in mice

Zhenhua Xu; Yanhong Wei; Junsong Gong; Hongkwan Cho; James K. Park; Ee Rah Sung; Hu Huang; Lijuan Wu; Charles Eberhart; James T. Handa; Yunpeng Du; Timothy S. Kern; Rajesh Thimmulappa; Alistair J. Barber; Shyam Biswal; Elia J. Duh

doi:10.1007/s00125-013-3093-8

NRF2 plays a protective role in diabetic retinopathy in mice

Zhenhua Xu, Yanhong Wei, Junsong Gong, Hongkwan Cho, James K. Park, Ee Rah Sung, Hu Huang, Lijuan Wu, Charles Eberhart, James T. Handa, Yunpeng Du, Timothy S. Kern, Rajesh Thimmulappa, Alistair J. Barber, Shyam Biswal, Elia J. Duh

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

106 Scopus citations

Abstract

Aims/hypothesis: Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Methods: Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. Results: NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. Conclusions/interpretation: These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.

Original language	English (US)
Pages (from-to)	204-213
Number of pages	10
Journal	Diabetologia
Volume	57
Issue number	1
DOIs	https://doi.org/10.1007/s00125-013-3093-8
State	Published - Jan 2014

Keywords

Diabetic retinopathy
Inflammation
Müller glial cells
NF-E2-related factor-2
Neuronal dysfunction
Reactive oxygen species
Transcription factor
Vascular permeability

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.1007/s00125-013-3093-8

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title = "NRF2 plays a protective role in diabetic retinopathy in mice",

abstract = "Aims/hypothesis: Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Methods: Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human M{\"u}ller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. Results: NRF2 was expressed prominently in M{\"u}ller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. Conclusions/interpretation: These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.",

keywords = "Diabetic retinopathy, Inflammation, M{\"u}ller glial cells, NF-E2-related factor-2, Neuronal dysfunction, Reactive oxygen species, Transcription factor, Vascular permeability",

author = "Zhenhua Xu and Yanhong Wei and Junsong Gong and Hongkwan Cho and Park, {James K.} and Sung, {Ee Rah} and Hu Huang and Lijuan Wu and Charles Eberhart and Handa, {James T.} and Yunpeng Du and Kern, {Timothy S.} and Rajesh Thimmulappa and Barber, {Alistair J.} and Shyam Biswal and Duh, {Elia J.}",

note = "Funding Information: Funding These studies were supported by research grants from the National Institutes of Health EY022383 (EJD), EY022683 (EJD) and EY019904 (JTH), the William & Ella Owens Medical Research Foundation and a generous gift from Cindy and Jeong H. Kim, PhD. EJD is a recipient of an RPB Career Development Award.",

year = "2014",

month = jan,

doi = "10.1007/s00125-013-3093-8",

language = "English (US)",

volume = "57",

pages = "204--213",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "1",

}

TY - JOUR

T1 - NRF2 plays a protective role in diabetic retinopathy in mice

AU - Xu, Zhenhua

AU - Wei, Yanhong

AU - Gong, Junsong

AU - Cho, Hongkwan

AU - Park, James K.

AU - Sung, Ee Rah

AU - Huang, Hu

AU - Wu, Lijuan

AU - Eberhart, Charles

AU - Handa, James T.

AU - Du, Yunpeng

AU - Kern, Timothy S.

AU - Thimmulappa, Rajesh

AU - Barber, Alistair J.

AU - Biswal, Shyam

AU - Duh, Elia J.

N1 - Funding Information: Funding These studies were supported by research grants from the National Institutes of Health EY022383 (EJD), EY022683 (EJD) and EY019904 (JTH), the William & Ella Owens Medical Research Foundation and a generous gift from Cindy and Jeong H. Kim, PhD. EJD is a recipient of an RPB Career Development Award.

PY - 2014/1

Y1 - 2014/1

N2 - Aims/hypothesis: Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Methods: Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. Results: NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. Conclusions/interpretation: These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.

AB - Aims/hypothesis: Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. Methods: Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. Results: NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. Conclusions/interpretation: These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.

KW - Diabetic retinopathy

KW - Inflammation

KW - Müller glial cells

KW - NF-E2-related factor-2

KW - Neuronal dysfunction

KW - Reactive oxygen species

KW - Transcription factor

KW - Vascular permeability

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SN - 0012-186X

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EP - 213

JO - Diabetologia

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ER -

NRF2 plays a protective role in diabetic retinopathy in mice

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