Abstract
BackgroundCumulative 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 FindingsEyes 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 microcopy both within the RPE and in Bruch's membrane of aged Nrf2−/− mice.ConclusionsOur 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.
Highlights
age-related macular degeneration (AMD) is the leading cause of severe visual impairment in elderly Americans, with an estimated 1.75 million people having advanced forms of the disease [1,2]
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration
To better understand the endogenous protective mechanisms that are involved in the different stages of retinal pigment epithelium (RPE)/choroid degeneration and choroidal neovascularization (CNV) development, we studied the agedependent retinal pathology in Nrf2 knockout mice
Summary
AMD is the leading cause of severe visual impairment in elderly Americans, with an estimated 1.75 million people having advanced forms of the disease [1,2]. NRF2 is a master regulator of endogenous antioxidant protection and is commonly involved in the transcriptional control of phase II detoxification enzymes [9]. It heterodimerizes with small Maf proteins and binds to the cis-acting antioxidant response element (ARE) sequence in the promoter regions of phase II genes [10]. Instead of relying on any single antioxidant enzyme, NRF2 activation leads to a concerted upregulation of a battery of protective proteins with coordinated functions at different steps of the detoxification process. The purposes of this study were to determine whether NRF2-deficient mice would develop AMDlike retinal pathology with aging and to explore the underlying mechanisms
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