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      Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells

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          Abstract

          Aims

          Blue light is an identified risk factor for age-related macular degeneration (AMD). We investigated oxidative stress markers and mitochondrial changes in A2E-loaded retinal pigment epithelium cells under the blue–green part of the solar spectrum that reaches the retina to better understand the mechanisms underlying light-elicited toxicity.

          Results

          Primary retinal pigment epithelium cells were loaded with a retinal photosensitizer, AE2, to mimic aging. Using a custom-made illumination device that delivers 10 nm-wide light bands, we demonstrated that A2E-loaded RPE cells generated high levels of both hydrogen peroxide (H 2O 2) and superoxide anion (O 2 •−) when exposed to blue–violet light. In addition, they exhibited perinuclear clustering of mitochondria with a decrease of both their mitochondrial membrane potential and their respiratory activities. The increase of oxidative stress resulted in increased levels of the oxidized form of glutathione and decreased superoxide dismutase (SOD) and catalase activities. Furthermore, mRNA expression levels of the main antioxidant enzymes (SOD2, catalase, and GPX1) also decreased.

          Conclusions

          Using an innovative illumination device, we measured the precise action spectrum of the oxidative stress mechanisms on A2E-loaded retinal pigment epithelium cells. We defined 415–455 nm blue–violet light, within the solar spectrum reaching the retina, to be the spectral band that generates the highest amount of reactive oxygen species and produces the highest level of mitochondrial dysfunction, explaining its toxic effect. This study further highlights the need to filter these wavelengths from the eyes of AMD patients.

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          Most cited references51

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          Prevalence of age-related maculopathy. The Beaver Dam Eye Study.

          The relationships of retinal drusen, retinal pigmentary abnormalities, and macular degeneration to age and sex were studied in 4926 people between the ages of 43 and 86 years who participated in the Beaver Dam Eye Study. The presence and severity of various characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. One or more drusen were present in the macular area of at least 1 eye in 95.5% of the population. People 75 years of age or older had significantly higher frequencies (P less than 0.01) of the following characteristics than people 43 to 54 years of age: larger sized drusen (greater than or equal to 125 microns, 24.0% versus 1.9%), soft indistinct drusen (23.0% versus 2.1%), retinal pigment abnormalities (26.6% versus 7.3%), exudative macular degeneration (5.2% versus 0.1%), and geographic atrophy (2.0% versus 0%). These data indicate signs of age-related maculopathy are common in people 75 years of age or older and may pose a substantial public health problem.
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            Oxidative damage and age-related macular degeneration.

            This article provides current information on the potential role of oxidation in relation to age-related macular degeneration (AMD). The emphasis is placed on the generation of oxidants and free radicals and the protective effects of antioxidants in the outer retina, with specific emphasis on the photoreceptor cells, the retinal pigment epithelium and the choriocapillaris. The starting points include a discussion and a definition of what radicals are, their endogenous sources, how they react, and what damage they may cause. The photoreceptor/pigment epithelium complex is exposed to sunlight, is bathed in a near-arterial level of oxygen, and membranes in this complex contain high concentrations of polyunsaturated fatty acids, all considered to be potential factors leading to oxidative damage. Actions of antioxidants such as glutathione, vitamin C, superoxide dismutase, catalase, vitamin E and the carotenoids are discussed in terms of their mechanisms of preventing oxidative damage. The phototoxicity of lipofuscin, a group of complex autofluorescent lipid/protein aggregates that accumulate in the retinal pigment epithelium, is described and evidence is presented suggesting that intracellular lipofuscin is toxic to these cells, thus supporting a role for lipofuscin in aging and AMD. The theory that AMD is primarily due to a photosensitizing injury to the choriocapillaris is evaluated. Results are presented showing that when protoporphyric mice are exposed to blue light there is an induction in the synthesis of Type IV collagen synthesis by the choriocapillary endothelium, which leads to a thickened Bruch's membrane and to the appearance of sub-retinal pigment epithelial fibrillogranular deposits, which are similar to basal laminar deposits. The hypothesis that AMD may result from oxidative injury to the retinal pigment epithelium is further evaluated in experiments designed to test the protective effects of glutathione in preventing damage to cultured human pigment epithelial cells exposed to an oxidant. Experiments designed to increase the concentration of glutathione in pigment epithelial cells using dimethylfumarate, a monofunctional inducer, are described in relation to the ability of these cells to survive an oxidative challenge. While all these models provide undisputed evidence of oxidative damage to the retinal pigment epithelium and the choriocapillaris that is both light- and oxygen-dependent, it nevertheless is still unclear at this time what the precise linkage is between oxidation-induced events and the onset and progression of AMD.
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              Prevalence of Age-related Maculopathy

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                Author and article information

                Contributors
                +33 1 53 46 25 04 , serge.picaud@inserm.fr
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                19 February 2018
                19 February 2018
                March 2018
                : 9
                : 3
                : 287
                Affiliations
                [1 ]Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
                [2 ]INSERM U1051 - Institut des Neurosciences de Montpellier, 34091 Montpellier, France
                [3 ]Essilor International R&D, 94220 Charenton-Le-Pont, France
                [4 ]CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS 1423, 75012 Paris, France
                [5 ]ISNI 0000 0001 2177 525X, GRID grid.417888.a, Fondation Ophtalmologique Rothschild, ; 75019 Paris, France
                [6 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Ophthalmology, , The University of Pittsburgh School of Medicine, ; Pittsburgh, PA 15213 USA
                [7 ]ISNI 0000 0001 2248 3363, GRID grid.7252.2, Equipe MitoLab, Pôle de Recherche et d’Enseignement en Médecine Mitochondriale, Institut MitoVasc, Université d’Angers, ; UMR CNRS 6015, INSERM U1083, 49933 Angers, France
                Article
                331
                10.1038/s41419-018-0331-5
                5833722
                29459695
                2cdbda6f-9a56-4ce2-a5b5-6feec2d5230b
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 November 2017
                : 9 January 2018
                : 11 January 2018
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                © The Author(s) 2018

                Cell biology
                Cell biology

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