Activation of GSDMD contributes to acute kidney injury induced by cisplatin
Activation of GSDMD contributes to acute kidney injury induced by cisplatin
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GSDMD 的激活导致顺铂诱导的急性肾损伤
DOI：
10.1152/ajprenal.00351.2019
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发表时间：
2020-01-01
影响因子：
4.2
通讯作者：
Jia, Zhanjun
中科院分区：
文献类型：
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作者：
Li, Yuanyuan;Xia, Weiwei;Jia, Zhanjun
顺铂是最有效的抗肿瘤药物之一，但其严重的副作用，特别是肾毒性，极大地限制了其临床应用。最近。 Gasdermin D (GSDMD) 的活性形式，称为 GSDMD-N，已被确定可介导多种疾病中的焦亡炎症细胞死亡。然而，GSDMD-N 片段在顺铂诱导的急性肾损伤 (AKI) 中的作用仍不清楚。在本研究中，我们发现顺铂在小鼠肾组织和肾小管上皮细胞中诱导细胞焦亡，并伴有 GSDMD-N 片段表达增加。在顺铂诱导 AKI 的 GSDMD 基因敲除小鼠中，我们发现与野生型小鼠相比，顺铂诱导的肾功能丧失、肾小管损伤和炎症显着减轻。此外，通过已建立的快速质粒尾静脉注射方法过表达 GSDMD-N 片段，以评估这种 GSDMD 切割形式在 AKI 中的作用。正如预期的那样，肾脏中 GSDMD-N 片段过表达的小鼠比对照小鼠更容易受到顺铂诱导的 AKI，血清尿素氮和肌酐水平进一步升高、肾脏病理加重、中性粒细胞明胶酶相关脂质运载蛋白和肾损伤分子 1 的表达增加以及肾脏炎症细胞因子增强就证明了这一点。 分泌，表明 GSDMD-N 通过触发细胞焦亡在顺铂诱导的 AKI 中发挥致病作用。在过表达 GSDMD-N 片段的肾小管上皮细胞中也观察到类似的结果。因此，这些发现表明 GSDMD 的激活可能通过引发细胞焦亡而导致顺铂诱导的 AKI。
Cisplatin is one of the most effective antitumor agents, but its clinical use is highly limited by its severe side effects, especially nephrotoxicity. Recently. the active form of gasdermin D (GSDMD), termed GSDMD-N, was identified to mediate pyroptotic inflammatory cell death in several diseases. However, the role of the GSDMD-N fragment in cisplatin-induced acute kidney injury (AKI) remains unclear. In the present study, we found that pyroptosis was induced by cisplatin in both mouse kidney tissues and renal tubular epithelial cells, accompanied by increased expression of the GSDMD-N fragment. In GSDMD knockout mice with cisplatin-induced AKI, we found that cisplatin-induced loss of renal function, renal tubular injury, and inflammation was significantly attenuated compared with wild-type mice. Furthermore, the GSDMD-N fragment was overexpressed by an established rapid plasmid tail vein injection approach to evaluate the role of this cleaved form of GSDMD in AKI. As expected, mice with GSDMD-N fragment overexpression in the kidney were more susceptible to cisplatin-induced AKI than control mice, as evidenced by further elevated serum levels of blood urea nitrogen and creatinine, aggravated renal pathology, increased expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and enhanced renal inflammatory cytokine secretion, which indicates a pathogenic role of GSDMD-N in cisplatin-induced AKI by triggering cell pyroptosis. Similar results were also observed in renal tubular epithelial cells overexpressing the GSDMD-N fragment. Thus these findings suggested that the activation of GSDMD contributes to cisplatin-induced AKI, possibly through triggering pyroptosis.