Caspase-11 Mediates Pyroptosis of Tubular Epithelial Cells and Septic Acute Kidney Injury
Caspase-11 Mediates Pyroptosis of Tubular Epithelial Cells and Septic Acute Kidney Injury
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Caspase-11 介导管状上皮细胞焦亡和脓毒性急性肾损伤
DOI：
10.1159/000499685
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发表时间：
2019-01-01
影响因子：
2.8
通讯作者：
Liang, Xinling
中科院分区：
文献类型：
--
作者：
Ye, Zhiming;Zhang, Li;Liang, Xinling
背景/目的：急性肾损伤（阿基）是脓毒症的严重并发症，具有较高的发病率和死亡率。胱天蛋白酶-11诱导焦亡，这是一种在内毒素休克中起关键作用的程序性细胞死亡形式，但其在肾小管上皮细胞死亡中的作用以及是否有助于脓毒症相关的阿基仍不清楚。方法：以caspase-11-/-小鼠为模型，腹腔注射脂多糖（LPS，40 mg/kg体重）。用LPS体外处理来自C57 BL caspase-11-/-小鼠的肾小管上皮细胞（RTECs）。采用IL-1β ELISA试剂盒和Scr测定试剂盒检测IL-1β和血清肌酐水平。采用Annexin V-FITC法和TUNEL法检测不同剂量组的细胞死亡情况。Western blot检测caspase-11和Gsdmdc 1蛋白的表达。结果如下：LPS诱导的脓毒症导致RTECs溶解性死亡，伴随着热解相关蛋白caspase-11和Gsdmd的表达增加。然而，在体外和体内，由LPS诱导的热解相关蛋白表达的增加被caspase-11敲除减弱。此外，当用致死剂量的全身性LPS攻击时，在野生型小鼠中观察到肾结构的病理异常、血清和肾脏白细胞介素-1 β增加、血清肌酐增加和动物死亡，但在半胱天冬酶-11-/-小鼠中得到预防。结论：Caspase-11诱导的RTECs的焦亡是脓毒症阿基期间的关键事件，靶向RTECs中的Caspase-11可作为脓毒症阿基的新治疗靶点。
Background/Aims: Acute kidney injury (AKI) is a serious complication of sepsis and has a high morbidity and mortality rate. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock, but its role in tubular epithelial cell death and whether it contributes to sepsis-associated AKI remains unknown. Methods: The caspase-11–/– mouse received an intraperitoneal injection of lipopolysaccharide (LPS, 40 mg/kg body weight). Caspase-11–/– renal tubular epithelial cells (RTECs) form C57BL caspase-11–/– mice were treated with LPS in vitro. The IL-1β ELISA kit and Scr assay kit were used to measure the level of interleukin-1β and serum creatinine. Annexin V-FITC assay and TUNEL staining assay were used to detect the cell death in different groups in vitro and in vivo. Western blot was performed to analyze the protein expression of caspase-11 and Gsdmdc1. Results: LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. However, the increase in pyroptosis-related protein expression induced by LPS was attenuated with caspase-11 knockout, both in vitro and in vivo. Furthermore, when challenged with lethal doses of systemic LPS, pathologic abnormalities in renal structure, increased serum and kidney interleukin-1β, increased serum creatinine, and animal death were observed in wild-type mice but prevented in caspase-11–/– mice. Conclusions: Caspase-11-induced pyroptosis of RTECs is a key event during septic AKI, and targeting of caspase-11 in RTECs may serve as a novel therapeutic target in septic AKI.