Abstract
Purpose: :
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 controlling the expression of antioxidant and detoxification genes. We hypothesize that mice deficient of Nrf2 are more vulnerable to oxidative damage especially in tissues with high oxygen consumption, such as the retina. The purpose of this study were to determine whether disruption of mouse Nrf2 would lead to retinal damage mimicking human AMD.
Methods: :
Eyes of both wild type and Nrf2 knockout mice were examined in vivo by fundus photography and electroretinography (ERG). Morphological examinations were performed under light and electron microscopy. Lipofuscin autofluorescence was examined on cryostat sections. Immunofluorescent staining was performed to detect the deposition of inflammatory proteins related to AMD.
Results: :
By 12-month of age, Nrf2 knockout mice developed drusen-like lesions and RPE changes resembling atrophic AMD, which were confirmed on fundus photography, and showed decreased a- and b-wave on ERG recording. Extensive RPE pathology, including hyper- and hypo-pigmentation, vacuolation, drusenoid deposition, and RPE cell loss, was observed by light microscopy in aged knockout mice. Electron microscopic changes, such as basal laminar deposits and , thickening of Bruch’s membrane and choriocapillaris, were evident at 12 months. About 19% of Nrf2 knockout mice developed spontaneous choroidal neovascularization, subretinal hemorrhage and exudative retinal detachment, which are hallmarks of neovascular AMD in humans. Furthermore, age dependent accumulation of lipofuscin autofluorescent material and deposition of immunological markers such as IgG, C3d and Serum Amyloid P was observed exclusively in the RPE and Bruch’s membrane of Nrf2 knockout mice.
Conclusions: :
Disruption of nrf2 gene increases the vulnerability of retina and RPE to oxidative damage. Mice deficient of Nrf2 developed ocular pathology similar to cardinal features of human AMD and will potentially provide a novel model for mechanistic and translational research.
Keywords: age-related macular degeneration • degenerations/dystrophies • retinal pigment epithelium