成年小鼠视网膜色素上皮特异性 GPx4 消减再现了老年性黄斑变性中地理萎缩的主要特征。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Kunihiro Azuma, Takafumi Suzuki, Kenta Kobayashi, Masako Nagahara, Hirotaka Imai, Akiko Suga, Takeshi Iwata, Tomoyasu Shiraya, Makoto Aihara, Takashi Ueta
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引用次数: 0

摘要

老年性黄斑变性(AMD)是导致老年人不可逆视力丧失的主要原因,尤其是被称为地理萎缩(GA)的晚期干性黄斑变性,缺乏有效的治疗方案。AMD的遗传小鼠模型揭示了脂质代谢和抗氧化能力受损在AMD早期/中期阶段的重要性,但在严重损害视觉功能的GA中的作用仍不明确。为了研究 RPE 中过氧化脂质与晚期干性 AMD 的潜在相关性,GPx4fl/fl 小鼠接受了 RPE 特异性 AAV-Cre 载体或对照 AAV 载体的视网膜下注射。RPE 特异性 GPx4 缺乏会导致 RPE 快速变性,这与晚期干性黄斑变性的主要特征相似,包括 RPE 细胞极性的先期丧失、丙烯醛、丙二醛和 4-羟基壬烯醛的积累、感光体的丧失、视网膜下含脂褐素的嗜黑体浸润以及补体激活。用α-生育酚和铁前列素-1治疗可减轻RPE变性,在GPx4缺乏的小鼠中可观察到线粒体萎缩,这表明铁突变参与其中。意想不到的是,坏死抑制剂 necrostatin-1s 也能改善 RPE 退化,并观察到 RIP3 和 MLKL 的激活以及 caspase-8 的失活,这表明铁氧化和坏死途径之间存在相互影响。我们的发现揭示了 AMD 中 RPE 退化的复杂机制,并强调 GPx4/脂质过氧化是潜在的治疗靶点。小鼠 RPE 特异性 GPx4 消融为进一步阐明脂质过氧化、细胞死亡途径和 AMD 发病机制之间的相互作用提供了宝贵的工具,为临床前研究和针对 GA 的治疗开发提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Retinal pigment epithelium-specific ablation of GPx4 in adult mice recapitulates key features of geographic atrophy in age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population, particularly the late-stage of dry AMD known as geographic atrophy (GA), lacks effective treatment options. Genetic mouse models of AMD have revealed the significance of impaired lipid metabolism and anti-oxidative capacity in early/intermediate stage of AMD, but remains unclear in GA that severely damages visual function. Here, to investigate the potential relevance of peroxidized lipids in RPE for late-stage dry AMD, GPx4fl/fl mice underwent subretinal injections of RPE-specific AAV-Cre vector or control AAV vector. RPE-specific GPx4 deficiency led to rapid RPE degeneration resembling key features of late-stage dry AMD, including preceding loss of RPE cell polarity, accumulation of acrolein, malondialdehyde, and 4-hydroxynonenal, photoreceptor loss, lipofuscin-laden subretinal melanophage infiltration, and complement activation. Treatment with α-tocopherol and ferrostatin-1 mitigated RPE degeneration, and shrunk mitochondria were observed in GPx4 deficient mice, suggesting involvement of ferroptosis. Unexpectedly, necrostatin-1s, an inhibitor of necroptosis, also ameliorated RPE degeneration, and activation of RIP3 and MLKL along with inactivation of caspase-8 was observed, indicating crosstalk between ferroptosis and necroptosis pathways. Our findings shed light on the intricate mechanisms underlying RPE degeneration in AMD and highlight GPx4/lipid peroxidation as potential therapeutic targets. RPE-specific ablation of GPx4 in mice provides a valuable tool for further elucidating the interplay between lipid peroxidation, cell death pathways, and AMD pathogenesis, offering new insights for preclinical research and therapeutic development targeting GA.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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