Retinal pigment epithelial cell necroptosis in response to sodium iodate.
Retinal pigment epithelial cell necroptosis in response to sodium iodate.
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DOI：
10.1038/cddiscovery.2016.54
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发表时间：
2016
影响因子：
7
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Hanus J;Anderson C;Sarraf D;Ma J;Wang S
老年性黄斑变性(AMD)是一种视网膜退行性疾病，是发达国家老年人致盲的主要原因。干性AMD的晚期，或称地理性萎缩(GA)，以广泛的视网膜色素上皮(RPE)变性为特征。GA中RPE细胞死亡的潜在分子机制尚不清楚。我们先前的研究已经证实，在体外，RPE细胞主要死于氧化应激引起的坏死性下垂。在这里，我们扩展了我们的研究，目的是在体外和NaIO3诱导的视网膜变性小鼠模型中，表征RPE细胞对碘酸钠(NaIO3)反应的死亡的性质。我们发现NaIO3通过一系列分子特征在体外诱导RPE坏死性下垂。通过原位末端标记法、活性caspase-3和HMGB1免疫组织化学染色证实，在体内，光感受器细胞主要死于凋亡，视网膜色素上皮细胞主要死于NaIO_3引起的坏死性下垂。RIPK1抑制剂Necrostatin-1的使用也支持该模型中的RPE坏死性下垂。此外，利用新的RIPK3-GFP转基因小鼠系，我们在注射NaIO3后的体内RPE细胞中检测到了RIPK3聚集，这是坏死性下垂的标志。我们的发现提示有必要重新评估AMD模型中RPE细胞的死亡机制，并有可能影响干性AMD，特别是GA的治疗发展。
Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in the elderly in developed countries. The late stage of dry AMD, or geographic atrophy (GA), is characterized by extensive retinal pigment epithelium (RPE) degeneration. The underlying molecular mechanism for RPE cell death in GA remains unclear. Our previous study has established that RPE cells die predominantly from necroptosis in response to oxidative stress in vitro. Here, we extend our study and aim to characterize the nature of RPE cell death in response to sodium iodate (NaIO3) in vitro and in a NaIO3-induced retina degeneration mouse model. We found that NaIO3 induces RPE necroptosis in vitro by using a combination of molecular hallmarks. By using TUNEL assays, active caspase-3 and HMGB1 immunostaining, we confirmed that photoreceptor cells die mainly from apoptosis and RPE cells die mainly from necroptosis in response to NaIO3 in vivo. RPE necroptosis in this model is also supported by use of the RIPK1 inhibitor, Necrostatin-1. Furthermore, using novel RIPK3-GFP transgenic mouse lines, we detected RIPK3 aggregation, a hallmark of necroptosis, in the RPE cells in vivo after NaIO3 injection. Our findings suggest the necessity of re-evaluating RPE cell death mechanism in AMD models and have the potential to influence therapeutic development for dry AMD, especially GA.