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Updated: Jun 2, 2026
A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration
Published on: March 10, 2023
Age-related retinopathy in NRF2-deficient mice
Zhenyang Zhao1, Yan Chen, Jian Wang
1Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Background:
Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.
Methods And Findings:
Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Conclusions:
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD.
Insights
Mice lacking the NRF2 gene showed AMD-like pathology with aging, including RPE degeneration and inflammation. This suggests NRF2 deficiency increases retinal vulnerability, with autophagy dysfunction potentially linking oxidative stress and inflammation in age-related macular degeneration.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Oxidative damage contributes to age-related macular degeneration (AMD) pathogenesis.
- Nuclear factor erythroid 2-related factor 2 (NRF2) regulates retinal antioxidant and detoxification pathways.
Purpose of the Study:
- To investigate if NRF2-deficient mice develop AMD-like pathology with aging.
- To explore the mechanisms underlying NRF2 deficiency-induced retinal degeneration.
Main Methods:
- Fundus photography and electroretinography (ERG) in wild type and Nrf2(-/-) mice.
- Light and electron microscopy, and immunofluorescence labeling for structural analysis.
- In vivo examination of ocular pathology in aged Nrf2(-/-) mice.
Main Results:
- Nrf2(-/-) mice exhibited age-dependent retinal pigment epithelium (RPE) degeneration.
- Development of drusen-like deposits, lipofuscin accumulation, and spontaneous choroidal neovascularization (CNV) in Nrf2(-/-) mice.
- Electron microscopy revealed autophagy-related vacuoles and multivesicular bodies in RPE and Bruch's membrane of aged Nrf2(-/-) mice.
Conclusions:
- NRF2 deficiency enhances outer retinal vulnerability to age-related degeneration.
- NRF2-deficient mice display key features of human AMD.
- Deregulated autophagy is a potential mechanism linking oxidative injury and inflammation in AMD.
