Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage.
Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage.
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DOI：
10.1016/j.exer.2014.04.009
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发表时间：
2014-06
影响因子：
3.4
通讯作者：
Ivanov, Dmitry
中科院分区：
文献类型：
--
作者：
Dvoriantchikova, Galina;Degterev, Alexei;Ivanov, Dmitry
视网膜缺血再灌注（IR）损伤仍然是失明的常见原因，并且具有通过凋亡和坏死导致视网膜神经节细胞（RGC）死亡的最终途径。 RGC 凋亡在 IR 损伤中得到了深入研究，而 RGC 坏死却没有得到足够的重视，因为它被视为一种意外且不受调控的细胞事件。然而，有证据表明，坏死与细胞凋亡一样，可以通过程序化机制来实现。在这项研究中，我们测试了 RGC 程序性坏死（坏死性凋亡）在 IR 诱导的视网膜损伤中的作用。我们采用视网膜IR损伤的小鼠模型进行体内实验。氧和葡萄糖剥夺（OGD）模型用作体外IR模型。通过免疫淘选技术分离原代 RGC。 Necrostatin 1 (Nec1) 用于在体外和体内实验中抑制坏死性凋亡。通过定量RT-PCR评估基因表达的变化。分别通过免疫组织化学和免疫细胞化学评估视网膜和 RGC 培养物中蛋白质的分布。我们的数据表明，启动坏死性凋亡的蛋白质（Ripk1 和 Ripk3）存在于正常和缺血性 RGC 中。 Nec1 治疗显着减少 IR 后的视网膜损伤。在 Nec1 处理的培养物中观察到 OGD 后 RGC 存活率增加和 RGC 坏死减少。我们发现，在 Nec1 治疗的缺血性视网膜中，编码促炎标记物 Il1b、Ccl5、Cxcl10、Nos2 和 Cybb 的基因表达显着降低。因此，我们的研究结果表明，RGC 坏死性凋亡通过细胞的直接损失和相关炎症反应的诱导，导致 IR 后的视网膜损伤。
Retinal ischemia–reperfusion (IR) injury remains a common cause of blindness and has a final pathway of retinal ganglion cell (RGC) death by apoptosis and necrosis. RGC apoptosis was intensively studied in IR injury, while RGC necrosis did not receive nearly enough consideration since it was viewed as an accidental and unregulated cellular event. However, there is evidence that necrosis, like apoptosis, can be implemented by a programmed mechanism. In this study, we tested the role of RGC programmed necrosis (necroptosis) in IR-induced retinal injury. We employed the mouse model of retinal IR injury for in vivo experiments. The oxygen and glucose deprivation (OGD) model was used as an IR model in vitro. Primary RGCs were isolated by an immunopanning technique. Necrostatin 1 (Nec1) was used to inhibit necroptosis in in vitro and in vivo experiments. The changes in gene expression were assessed by quantitative RT-PCR. The distribution of proteins in the retina and in RGC cultures was evaluated by immunohistochemistry and immunocytochemistry, respectively. Our data suggest that proteins (Ripk1 and Ripk3), which initiate necroptosis, were present in normal and ischemic RGCs. Treatment with Nec1 significantly reduced retinal damage after IR. Increased RGC survival and reduced RGC necrosis following OGD were observed in Nec1-treated cultures. We found significantly reduced expression of genes coding pro-inflammatory markers Il1b, Ccl5, Cxcl10, Nos2 and Cybb in Nec1-treated ischemic retinas. Thus, our findings suggest that RGC necroptosis contributes to retinal damage after IR through direct loss of cells and induction of associated inflammatory responses.
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