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David M Wu, Xuke Ji, Wenjun Xiong, Constance L Cepko; Overexpression of Nrf2 in the eye protects retinal pigment epithelial cells of Rd1 mice. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1186.
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© ARVO (1962-2015); The Authors (2016-present)
The Nrf2 pathway is a key regulator of protection against oxidative stress in many systems, including the eye. Nrf2-/- mice have been shown to have an eye phenotype reminiscent to age-related macular degeneration. Conversely, overexpression of Nrf2 with an adeno-associated virus (AAV) in cone photoreceptors has been shown to rescue these cells from death in the rd1 model of retinitis pigmentosa. As this AAV also infects the retinal pigment epithelium (RPE), we sought to determine the effect of overexpression of Nrf2 on retinal pigment epithelial cells in rd1 mice.
AAV vectors (serotype 8) were delivered by subretinal injection at P0 in rd1 mice. AAVs expressing green fluorescent protein (GFP) driven by a cytomegalovirus (CMV) promoter [CMV GFP] and/or Nrf2 driven by a CMV promoter [CMV Nrf2] were used. Mice were then sacrificed at serial time points and examined for histological analysis.
In control mice that only received subretinal injections of CMV GFP, RPE cells appeared dysmorphic and even absent in some areas by P30. In contrast, mice that received subretinal coinjections of CMV Nrf2 and CMV GFP showed preservation of the RPE. In a subset of mice, in which subretinal injections resulted in only partial coverage of the eye, areas of dysmorphic versus preserved structure correlated well with uninfected versus infected RPE, respectively.
Overexpression of Nrf2 using the CMV promoter in cone photoreceptors has previously been shown to prolong their survival in the rd1 mouse model of retinal degeneration. In this study, we show that the same route of Nrf2 delivery (subretinal injection) also results in a protective effect on the retinal pigment epithelium. Because the CMV promoter is serendipitously expressed at high levels in both RPE as well as cones, this may be due to the autonomous effects of Nrf2 in the RPE. Alternatively, it may be a secondary (non-autonomous) effect of over-expression of Nrf2 in the cones. We are now undertaking studies with AAVs that have higher degrees of photoreceptor or RPE specificy of expression in order to better understand the mechanism of RPE rescue by CMV Nrf2.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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