title: NRF2 plays a protective role in diabetic retinopathy in mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Junsong
authors.initials: J
authors.lastname: Gong
authors.forename: Hongkwan
authors.initials: H
authors.lastname: Cho
authors.forename: James K
authors.initials: JK
authors.lastname: Park
authors.forename: Ee-Rah
authors.initials: ER
authors.lastname: Sung
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wu
authors.forename: Charles
authors.initials: C
authors.lastname: Eberhart
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Du
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Rajesh
authors.initials: R
authors.lastname: Thimmulappa
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Barber
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
mesh_terms: D000818:Animals; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species