Inflammation and tubular cell death are the hallmarks of acute kidney injury. However, the precise mechanism underlying these effects has not been fully elucidated. Here we tested whether caspase-11, an inflammatory member of the caspase family, was increased in cisplatin or ischemia-reperfusion-induced acute kidney injury. Caspase-11 knockout mice after cisplatin treatment exhibited attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion. Mechanistically, the upregulation of caspase-11 by either cisplatin or ischemia-reperfusion cleaved gasdermin D (GSDMD) into GSDMD-N, which translocated onto the plasma membrane, thus triggering cell pyroptosis and facilitated IL-18 release in primary cultured renal tubular cells. These results were further confirmed in GSDMD knockout mice that cisplatin-induced renal morphological and functional deterioration as well as urinary IL-18 excretion were alleviated. Furthermore, deficiency of GSDMD significantly suppressed cisplatin-induced IL-18 release but not the transcription and maturation level of IL-18 in tubular cells. Thus, our study indicates that caspase-11/GSDMD dependent tubule cell pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury.

炎症和肾小管细胞死亡是急性肾损伤的标志。但是，尚未完全阐明造成这些影响的确切机制。在这里，我们测试了caspase家族中的一个炎症成员caspase-11在顺铂或缺血再灌注诱导的急性肾损伤中是否增加。顺铂处理后的Caspase-11基因敲除小鼠表现出减弱的肾功能恶化，肾小管损伤减少，巨噬细胞和中性粒细胞浸润减少以及尿液IL-18排泄减少。从机制上讲，顺铂或缺血再灌注裂解的gasdermin D（GSDMD）将caspase-11上调至GSMDD-N，后者转移到质膜上，从而触发细胞凋亡，并促进原代培养肾小管细胞中IL-18的释放。这些结果在GSDMD基因敲除小鼠中得到进一步证实，顺铂诱导的肾脏形态和功能恶化以及尿液IL-18排泄得到缓解。此外，GSDMD的缺乏显着抑制了顺铂诱导的IL-18释放，但没有抑制管状细胞中IL-18的转录和成熟水平。因此，我们的研究表明，在急性肾损伤中，依赖caspase-11 / GSDMD的肾小管细胞凋亡在引发肾小管细胞损伤，尿IL-18排泄和肾功能恶化中起着重要作用。GSDMD的缺乏会显着抑制顺铂诱导的IL-18释放，但不能抑制小管细胞中IL-18的转录和成熟水平。因此，我们的研究表明，在急性肾损伤中，依赖caspase-11 / GSDMD的肾小管细胞凋亡在引发肾小管细胞损伤，尿IL-18排泄和肾功能恶化中起着重要作用。GSDMD的缺乏显着抑制顺铂诱导的IL-18释放，但不能抑制小管细胞中IL-18的转录和成熟水平。因此，我们的研究表明，在急性肾损伤中，依赖caspase-11 / GSDMD的肾小管细胞凋亡在引发肾小管细胞损伤，尿IL-18排泄和肾功能恶化中起着重要作用。