Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis
Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis
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DOI：
10.1073/pnas.1009179107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Vavvas, Demetrios G.
中科院分区：
文献类型：
--
作者：
Trichonas, George;Murakami, Yusuke;Vavvas, Demetrios G.
在许多疾病中，细胞凋亡已被证明是细胞丢失的一种重要形式。光感受器从视网膜色素上皮分离，如在各种视网膜疾病中所见，导致光感受器丧失和随后的视力下降。尽管caspase依赖的凋亡通路在视网膜脱离后被激活，但用泛caspase抑制剂Z-VAD抑制caspase并不能阻止光感受器死亡；因此，我们研究了导致细胞丢失的其他途径。在此，我们发现受体相互作用蛋白(RIP)激酶介导的坏死是视网膜脱离实验模型中光感受器细胞丢失的一种重要方式，当caspase被抑制时，RIP介导的坏死成为主要的死亡形式。视网膜脱离后，RIP1激酶的关键激活物RIP3的表达增加了10倍以上。Z-VAD治疗后视网膜脱离的形态学评估显示，细胞凋亡减少，但坏死性光感受器死亡明显增加。RIP1激酶抑制剂Necrostatin-1或RIP3缺乏实质上阻止了这些坏死性改变，并减少了氧化应激和线粒体凋亡诱导因子的释放。因此，RIP激酶介导的程序性坏死是光感受器死亡的一种除细胞凋亡之外的多余机制，同时抑制RIP激酶和caspase对于有效的神经保护是必不可少的，并可能成为治疗视网膜疾病的一种新的治疗策略。
Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders.