NRF2 plays a protective role in diabetic retinopathy in mice

• Published in: Diabetologia Vol. 57; no. 1; pp. 204 - 213
• Main Authors: Xu, Zhenhua, Wei, Yanhong, Gong, Junsong, Cho, Hongkwan, Park, James K., Sung, Ee-Rah, Huang, Hu, Wu, Lijuan, Eberhart, Charles, Handa, James T., Du, Yunpeng, Kern, Timothy S., Thimmulappa, Rajesh, Barber, Alistair J., Biswal, Shyam, Duh, Elia J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2014; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Cell Line; Diabetes; Diabetes. Impaired glucose tolerance; Diabetic retinopathy; Diabetic Retinopathy - genetics; Diabetic Retinopathy - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Gene expression; Human Physiology; Humans; Inflammation; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Mutant Strains; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Ophthalmology; Oxidative stress; Oxidative Stress - genetics; Oxidative Stress - physiology; Pathogenesis; Reactive Oxygen Species - metabolism; Retina - metabolism; Retina - pathology; Retinopathies; Transcription factors; Vascular endothelial growth factor; Vertebrates: nervous system and sense organs; United States > US; Baltimore Maryland; Diabetic retinopathy; Reactive oxygen species; Inflammation; Neuronal dysfunction; Transcription factor; Müller glial cells; NF-E2-related factor-2; Vascular permeability; Endocrinopathy; Retinopathy; Neuroglia; Retina; Eye; Visual system; Glial cell; Diabetes mellitus; Rodentia; Muller cell; Permeability; Eye disease; Vertebrata; Mammalia; Mouse; Dysfunction; Animal
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-3093-8

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.