Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway
Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway
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DOI：
10.1152/ajprenal.00117.2013
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
He, Ya-Ni
中科院分区：
文献类型：
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作者：
Yang, Ju-Rong;Yao, Feng-Hua;He, Ya-Ni
肾小管上皮细胞凋亡或坏死性死亡是肾缺血再灌注性急性肾损伤(AKI)的主要发病机制。上睑下垂是一种程序性细胞死亡途径，依赖于caspase级联和IL-1细胞因子家族成员的激活。然而，上睑下垂在脑缺血再灌流所致AKI中的作用尚不清楚。在本研究中，我们发现在肾缺血再灌注损伤(IRI)后6h，上睑下垂相关蛋白caspase-1、caspase-11和IL-1β的水平显著升高，并在IRI后12h达到高峰。增强性上睑下垂伴有肾脏结构和功能损伤。同样，低氧-复氧损伤(HRI)也可诱导肾小管上皮细胞NRK-52E发生热下垂，表现为气孔形成增多，乳酸脱氢酶释放增加。此外，内质网应激生物标记物葡萄糖调节蛋白78和C/EBP同源蛋白(CHOP)的明显上调先于IRI或HRI处理的细胞发生下垂。用小剂量衣霉素(内质网应激诱导剂)预处理可减轻IRI诱导的下垂和肾组织损伤。小干扰RNA沉默CHOP可显著降低HRI诱导的NRK-52E细胞的下垂，表现为caspase-11活性和IL-1β的产生减少。因此，我们得出结论，肾小管上皮细胞的下垂是IRI过程中的一个关键事件，而由过度激活的内质网应激所触发的CHOP-caspase-11可能是参与下垂发生的重要途径。
The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1 beta, were significantly increased after 6 h of renal ischemiareperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1 beta generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.