Lack of the P2X7 receptor protects against AMD-like defects and microparticle accumulation in a chronic oxidative stress-induced mouse model of AMD
Lack of the P2X7 receptor protects against AMD-like defects and microparticle accumulation in a chronic oxidative stress-induced mouse model of AMD
复制标题
DOI：
10.1016/j.bbrc.2016.10.140
复制
发表时间：
2017-01-01
影响因子：
3.1
通讯作者：
Yang, Dongli
中科院分区：
文献类型：
--
作者：
Carver, Kyle A.;Lin, C. M.;Yang, Dongli
P2X(7)受体（P2X(7)R）是一个atp门控离子通道，是病理条件下氧化应激的关键参与者。P2X(7)R在视网膜色素上皮（RPE）和神经视网膜中表达。慢性氧化应激有助于老年性黄斑变性（AMD）的发病机制。缺乏Cu， Zn超氧化物歧化酶（Sod1）的小鼠出现慢性氧化应激和AMD样特征，但P2X(7)R是否在氧化应激诱导的AMD中起致病作用尚不清楚。因此，本研究的主要目的是测试P2X(7)R的并发敲除（KO）是否可以阻断Sod1 KO小鼠中出现的amd样缺陷。通过多种方法，我们证明了Sod1 KO导致amd样缺陷，包括氧化应激标志物、3-硝基酪氨酸和羧甲基赖氨酸的阳性染色、RPE和视网膜变薄、Bruch膜增厚、基底层流和线状沉积物的存在、RPE屏障破坏和小胶质细胞/巨噬细胞的积累。此外，我们发现Sod1 KO小鼠在RPE/脉络膜组织中积累了更多的微粒（MPs）。P2X(7)R的并发KO可以防止Sod1 KO小鼠的amd样缺陷和MP积累。总之，我们首次表明，P2X7R的缺乏可以防止体内氧化应激诱导的MPs和amd样缺陷的积累。这项工作可能会导致AMD和其他氧化应激驱动疾病的新疗法。(C) 2016年作者。Elsevier Inc.出版。
The P2X(7) receptor (P2X(7)R) is an ATP-gated ion channel that is a key player in oxidative stress under pathological conditions. The P2X(7)R is expressed in the retinal pigmented epithelium (RPE) and neural retina. Chronic oxidative stress contributes to the pathogenesis of age-related macular degeneration (AMD). Mice lacking Cu, Zn superoxide dismutase (Sod1) developed chronic oxidative stress as well as AMD-like features, but whether the P2X(7)R plays a causative role in oxidative stress-induced AMD is unknown. Thus, the main purpose of this study was to test if concurrent knockout (KO) of P2X(7)R could block AMD-like defects seen in Sod1 KO mice. Using multiple approaches, we demonstrate that Sod1 KO causes AMD-like defects, including positive staining for oxidative stress markers, 3-nitrotyrosine and carboxymethyl lysine, thinning of the RPE and retina, thickening of Bruch's membrane, presence of basal laminar and linear deposits, RPE barrier disruption and accumulation of microglia/macrophages. Moreover, we find that Sod1 KO mice accumulate more microparticles (MPs) within RPE/choroid tissues. Concurrent KO of the P2X(7)R protects against AMD-like defects and MP accumulation in Sod1 KO mice. Together, we show for the first time, that deficiency of P2X7R prevents in vivo oxidative stress-induced accumulation of MPs and AMD-like defects. This work could potentially lead to novel therapies for AMD and other oxidative stress-driven diseases. (C) 2016 The Authors. Published by Elsevier Inc.