Abstract
Iron has been implicated in the pathogenesis of retinal degenerative diseases, including ocular siderosis. However, the mechanisms of iron-induced retinal toxicity are incompletely understood. Previous work shows that intravitreal injection of Fe2+ leads to photoreceptor (PR) oxidative stress, resulting in PR death within 14 days, and cones are more susceptible than rods to iron-induced oxidative damage. In order to further investigate the mechanism of intravitreal iron-induced retinal toxicity and shed light on mechanisms of iron-induced retinopathy in other mouse models, Fe2+, Fe3+, or saline were injected into the vitreous of adult wild-type mice. Pre-treatment with Ferrostatin-1 was used to investigate whether iron-induced retinal toxicity resulted from ferroptosis. Color and autofluorescence in vivo retinal imaging and optical coherence tomography were performed on day 2 and day 7 post-injection. Eyes were collected for quantitative PCR and Western analysis on day 1 and for immunofluorescence on both day 2 and 7. In vivo imaging and immunofluorescence revealed that Fe2+, but not Fe3+, induced PR oxidative damage and autofluorescence on day 2, resulting in PR death and retinal pigment epithelial cell (RPE) autofluorescence on day 7. Quantitative PCR and Western analysis on day 1 indicated that both Fe2+ and Fe3+ induced iron accumulation in the retina. However, only Fe2+ elevated levels of oxidative stress markers and components of ferroptosis in the retina, and killed PRs. Ferrostatin-1 failed to protect the retina from Fe2+-induced oxidative damage. To investigate the mechanism of Fe2+-induced RPE autofluorescence, rd10 mutant mice aged 6 weeks, with almost total loss of PRs, were given intravitreal Fe2+ or Fe3+ injections: neither induced RPE autofluorescence. This result suggests Fe2+-induced RPE autofluorescence in wild-type mice resulted from phagocytosed, oxidized outer segments. Together these data suggest that intraretinal Fe2+ causes PR oxidative stress, leading to PR death and RPE autofluorescence.
Highlights
Iron is essential for retinal metabolism, and significant for phototransduction
In vivo fundus imaging and Optical coherence tomography (OCT) was used to investigate the retinal phenotype after Fe2+ or Fe3+ intravitreal injection compared to saline control
Previous studies showed that Fe2+ intravitreal injection leads to oxidative stress in the retina, resulting in PR degeneration [22]
Summary
Iron is essential for retinal metabolism, and significant for phototransduction. Photoreceptors (PRs) shed and regenerate disc membranes, using the iron-containing enzyme fatty acid desaturase to synthesize lipids used in disc membrane generation. RPE65 is an iron-dependent enzyme used by the retinal pigment epithelium (RPE) to catalyze the conversion of all-trans-retinyl ester to 11cis-retinol, a critical step in the visual cycle [1]. Excess iron is toxic to the retina. Ferrous iron (Fe2+) can catalyze the conversion of hydrogen peroxide to hydroxyl radical, the highly reactive oxygen species (ROS), causing oxidative damage to DNA, proteins, and lipids [2]. PR outer segments, which are phagocytosed by RPE each day, are rich in oxidized lipids. Iron must be regulated tightly to provide sufficient iron while protecting retinal cells, especially PRs and RPE cells, from oxidative damage
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