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 G Eberhart, James Handa, Yunpeng Du, Timothy S. Kern, Rajesh Thimmulappa, Alistair J. Barber, Shyam Biswal, Elia J Duh

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)204-213
Number of pages10
JournalDiabetologia
Volume57
Issue number1
DOIs
StatePublished - Jan 2014

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Diabetic Retinopathy
Knockout Mice
Oxidative Stress
Retina
NF-E2 Transcription Factor
tert-Butylhydroperoxide
Gene Expression
Streptozocin
Oxidants
Neuroglia
Superoxides
Astrocytes
Hydrogen Peroxide
Glutathione
Reactive Oxygen Species
Anti-Inflammatory Agents
Antioxidants
Immunohistochemistry
Cell Line
Proteins

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

NRF2 plays a protective role in diabetic retinopathy in mice. / Xu, Zhenhua; Wei, Yanhong; Gong, Junsong; Cho, Hongkwan; Park, James K.; Sung, Ee Rah; Huang, Hu; Wu, Lijuan; Eberhart, Charles G; Handa, James; Du, Yunpeng; Kern, Timothy S.; Thimmulappa, Rajesh; Barber, Alistair J.; Biswal, Shyam; Duh, Elia J.

In: Diabetologia, Vol. 57, No. 1, 01.2014, p. 204-213.

Research output: Contribution to journalArticle

Xu, Z, Wei, Y, Gong, J, Cho, H, Park, JK, Sung, ER, Huang, H, Wu, L, Eberhart, CG, Handa, J, Du, Y, Kern, TS, Thimmulappa, R, Barber, AJ, Biswal, S & Duh, EJ 2014, 'NRF2 plays a protective role in diabetic retinopathy in mice', Diabetologia, vol. 57, no. 1, pp. 204-213. https://doi.org/10.1007/s00125-013-3093-8
Xu, Zhenhua ; Wei, Yanhong ; Gong, Junsong ; Cho, Hongkwan ; Park, James K. ; Sung, Ee Rah ; Huang, Hu ; Wu, Lijuan ; Eberhart, Charles G ; Handa, James ; Du, Yunpeng ; Kern, Timothy S. ; Thimmulappa, Rajesh ; Barber, Alistair J. ; Biswal, Shyam ; Duh, Elia J. / NRF2 plays a protective role in diabetic retinopathy in mice. In: Diabetologia. 2014 ; Vol. 57, No. 1. pp. 204-213.
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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.",
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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 G

AU - Handa, James

AU - Du, Yunpeng

AU - Kern, Timothy S.

AU - Thimmulappa, Rajesh

AU - Barber, Alistair J.

AU - Biswal, Shyam

AU - Duh, Elia J

PY - 2014/1

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KW - Reactive oxygen species

KW - Transcription factor

KW - Vascular permeability

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