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NRF2 plays a protective role in diabetic retinopathy in mice
Zhenhua Xu1, Yanhong Wei, Junsong Gong
1Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA.
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.
Insights
The nuclear factor erythroid-2-related factor 2 (NRF2) pathway plays a protective role in diabetic retinopathy (DR). Enhancing NRF2 may be a therapeutic strategy for DR.
Area of Science:
- Ophthalmology
- Neuroscience
- Molecular Biology
Background:
- Diabetic retinopathy (DR) pathogenesis is complex, with protective pathways understudied.
- Nuclear factor erythroid-2-related factor 2 (NRF2) is a key regulator of oxidative stress and inflammation.
- The role of NRF2 in DR progression requires further investigation.
Purpose of the Study:
- To investigate the role of NRF2 as a protective mechanism in diabetic retinopathy.
- To explore NRF2 expression and function in retinal cells and in vivo models of DR.
Main Methods:
- Immunohistochemistry to assess NRF2 expression in human and mouse retinas.
- In vitro studies using Müller cells (MIO-M1) to evaluate NRF2's effect on oxidative stress.
- In vivo studies using wild-type and Nrf2 knockout mice under diabetic conditions to assess DR endpoints.
Main Results:
- NRF2 is expressed in Müller glial cells and astrocytes in human and mouse retinas.
- NRF2 inhibition decreased antioxidant gene expression and worsened oxidative stress in vitro.
- Diabetic Nrf2 knockout mice showed increased oxidative stress, blood-retina barrier dysfunction, and neuronal dysfunction compared to wild-type controls.
Conclusions:
- NRF2 is a crucial protective factor in regulating diabetic retinopathy progression.
- Activation of the NRF2 pathway presents a potential therapeutic strategy for managing DR.
