NRF2/ARE mediated antioxidant response to glaucoma: role of glia and retinal ganglion cells.

TitleNRF2/ARE mediated antioxidant response to glaucoma: role of glia and retinal ganglion cells.
Publication TypeJournal Article
Year of Publication2023
AuthorsNaguib S, Backstrom JR, Artis E, Ghose P, Stahl A, Hardin R, Haider AA, Ang J, Calkins DJ, Rex TS
JournalActa Neuropathol Commun
Date Published2023 Oct 24
KeywordsAnimals, Antioxidant Response Elements, Antioxidants, Disease Models, Animal, Glaucoma, Intraocular Pressure, Mice, Neuroglia, NF-E2-Related Factor 2, Retinal Ganglion Cells

Glaucoma, the second leading cause of irreversible blindness worldwide, is associated with age and sensitivity to intraocular pressure (IOP). We have shown that elevated IOP causes an early increase in levels of reactive oxygen species (ROS) in the microbead occlusion mouse model. We also detected an endogenous antioxidant response mediated by Nuclear factor erythroid 2-Related Factor 2 (NRF2), a transcription factor that binds to the antioxidant response element (ARE) and increases transcription of antioxidant genes. Our previous studies show that inhibiting this pathway results in earlier and greater glaucoma pathology. In this study, we sought to determine if this endogenous antioxidant response is driven by the retinal ganglion cells (RGCs) or glial cells. We used Nrf2fl/fl mice and cell-type specific adeno-associated viruses (AAVs) expressing Cre to alter Nrf2 levels in either the RGCs or glial cells. Then, we quantified the endogenous antioxidant response, visual function and optic nerve histology after IOP elevation. We found that knock-down of Nrf2 in either cell type blunts the antioxidant response and results in earlier pathology and vision loss. Further, we show that delivery of Nrf2 to the RGCs is sufficient to provide neuroprotection. In summary, both the RGCs and glial cells contribute to the antioxidant response, but treatment of the RGCs alone with increased Nrf2 is sufficient to delay onset of vision loss and axon degeneration in this induced model of glaucoma.

Alternate JournalActa Neuropathol Commun
PubMed ID37875948
PubMed Central IDPMC10594672
Grant ListR01 EY022349 / EY / NEI NIH HHS / United States
R01 EY021833 / EY / NEI NIH HHS / United States
U24 EY029893 / EY / NEI NIH HHS / United States
P30 EY008126 / EY / NEI NIH HHS / United States
U24 EY029903 / EY / NEI NIH HHS / United States
R01 EY017427 / EY / NEI NIH HHS / United States