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01.01.2014 | Article

NRF2 plays a protective role in diabetic retinopathy in mice

verfasst von: 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

Erschienen in: Diabetologia | Ausgabe 1/2014

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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 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.

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Titel: NRF2 plays a protective role in diabetic retinopathy in mice
verfasst von: 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
Publikationsdatum: 01.01.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 1/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3093-8

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