mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
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DOI：
10.1172/jci44303
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发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Vollrath, Douglas
中科院分区：
文献类型：
--
作者：
Zhao, Chen;Yasumura, Douglas;Vollrath, Douglas
视网膜色素上皮 (RPE) 细胞功能障碍在各种视网膜退行性疾病中起着核心作用，但知识 1，关于体内成人 RPE 应激反应的途径有限 RPE 线粒体功能障碍与几种形式的视网膜变性的发病机制有关这里我们已经证明，出生后 RPE 线粒体氧化的消融 小鼠中的磷酸化会引发上皮逐渐去分化，典型表现为 RPE 特征蛋白减少和细胞肥大 视网膜对光的电反应减弱，光感受器最终退化 异常 RPE 细胞行为与糖酵解增加以及肝细胞生长因子/met 原癌基因途径 RPE 的激活和依赖有关 通过刺激 AKT/哺乳动物雷帕霉素靶点 (AKT/mTOR) 途径引起去分化和肥大 对野生型小鼠施用氧化剂也引起 RPE 去分化和 mTOR 激活 重要的是，用 mTOR 抑制剂雷帕霉素治疗削弱了去分化的关键方面并保留了两种损伤的光感受器功能 这些结果表明 成熟 RPE 对多种应激源的体内反应，以牺牲上皮属性和光感受器功能为代价延长 RPE 细胞的存活 我们的研究结果为 mTOR 通路抑制作为涉及 RPE 应激的视网膜退行性疾病的治疗策略提供了理论基础
Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge 1, limited regarding the pathways responsible for adult RPE stress responses in vivo RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE characteristic proteins and cellular hypertrophy The electrical response of the retina to light decreased and photoreceptors eventually degenerated Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto oncogene pathway RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation Importantly, treatment with the mTOR Inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress