Investigative ophthalmology & visual science · 2025
iPLA2β Protects Retinal Pigment Epithelium From Ferroptosis in a Sodium Iodate-Induced Model of Dry AMD.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Suzuki Takafumi, Terao Ryo, Nagahara Masako, Hayashi Kentaro, Azuma Kunihiro, Shinzawa Koei, Moriwaki Kenta, Shiraya Tomoyasu, Honjo Megumi, Ueta Takashi
Аннотация
PURPOSE: Ferroptosis, characterized by lipid peroxidation, has been implicated in retinal pigment epithelium (RPE) degeneration in dry age-related macular degeneration (AMD). This study aimed to investigate the role of calcium-independent phospholipase A2 group VI (iPLA2β) in protecting RPE cells from oxidative stress using a sodium iodate (NaIO3)-induced dry AMD model.
METHODS: The iPLA2β knockout (KO) and wild-type (WT) mice were subjected to NaIO3 administration. Retinal structure and function were evaluated by histology and electroretinography. The involvement of ferroptosis was assessed by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Pharmacological intervention experiments used ferrostatin-1, α-tocopherol, and necrostatin-1s to evaluate protective effects. Western blotting was performed for RIP3 phosphorylation, and RIP3 KO mice were used to further assess necroptosis involvement.
RESULTS: The iPLA2β KO mice exhibited normal retinal morphology and function under baseline conditions. NaIO3 exposure caused pronounced RPE and photoreceptor degeneration, a characteristic downregulation of genes responsive to ferroptotic stress, elevated lipid peroxidation, and impaired visual function, which were markedly rescued by ferrostatin-1 and α-tocopherol, and partially by necrostatin-1s. NaIO3 did not induce RIP3 phosphorylation, and necrostatin-1s appeared to exert antioxidative effects. RIP3 KO mice developed severe RPE degeneration after NaIO3 exposure, significantly attenuated by necrostatin-1s. These findings indicate that lipid peroxidation-mediated ferroptosis, rather than necroptosis, is the primary mechanism of NaIO3-induced retinal degeneration, particularly at low doses of NaIO3.
CONCLUSIONS: The iPLA2β functions as a key suppressor of lipid peroxidation-mediated RPE degeneration in the NaIO3 model. Targeting ferroptosis-particularly via iPLA2β-may represent a potential therapeutic approach for protecting the RPE from oxidative stress-induced injury in dry AMD, although further validation in human tissues will be necessary.
METHODS: The iPLA2β knockout (KO) and wild-type (WT) mice were subjected to NaIO3 administration. Retinal structure and function were evaluated by histology and electroretinography. The involvement of ferroptosis was assessed by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Pharmacological intervention experiments used ferrostatin-1, α-tocopherol, and necrostatin-1s to evaluate protective effects. Western blotting was performed for RIP3 phosphorylation, and RIP3 KO mice were used to further assess necroptosis involvement.
RESULTS: The iPLA2β KO mice exhibited normal retinal morphology and function under baseline conditions. NaIO3 exposure caused pronounced RPE and photoreceptor degeneration, a characteristic downregulation of genes responsive to ferroptotic stress, elevated lipid peroxidation, and impaired visual function, which were markedly rescued by ferrostatin-1 and α-tocopherol, and partially by necrostatin-1s. NaIO3 did not induce RIP3 phosphorylation, and necrostatin-1s appeared to exert antioxidative effects. RIP3 KO mice developed severe RPE degeneration after NaIO3 exposure, significantly attenuated by necrostatin-1s. These findings indicate that lipid peroxidation-mediated ferroptosis, rather than necroptosis, is the primary mechanism of NaIO3-induced retinal degeneration, particularly at low doses of NaIO3.
CONCLUSIONS: The iPLA2β functions as a key suppressor of lipid peroxidation-mediated RPE degeneration in the NaIO3 model. Targeting ferroptosis-particularly via iPLA2β-may represent a potential therapeutic approach for protecting the RPE from oxidative stress-induced injury in dry AMD, although further validation in human tissues will be necessary.