NRF2/ARE mediated antioxidant response to glaucoma: role of glia and retinal ganglion cells
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 24, 2023
- Source ID
- 10.1186/s40478-023-01663-1
Entities
People
- Ameer A. Haider
- Amy Stahl
- David J. Calkins
- Elisabeth Artis
- John Ang
- Jon R. Backstrom
- Purnima Ghose
- Rachael Hardin
- Sarah Naguib
- Tonia S. Rex
Organizations
- National Eye Institute
- United States Department of Defense