Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University , Shanghai , China.
Department of Nephrology, Shanghai Tong Ren Hospital , Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Am J Physiol Renal Physiol. 2018 Feb 1;314(2):F269-F279. doi: 10.1152/ajprenal.00091.2017. Epub 2017 Apr 26.
Renal tubular injury is the hallmark of cisplatin-induced nephrotoxicity. Caspase-11, a member of the caspase family, plays an important role in inflammation and cell death. However, its role in cisplatin-induced renal tubular injury remains unclear. In cisplatin-treated mice, caspase-11 expression was significantly elevated and the expression of caspase-11 was mainly located in renal tubule. Inhibition of caspase-11 by small-interference RNA or its inhibitor wedelolactone attenuated cisplatin-induced renal dysfunction and tubular injury. In cultured primary renal tubular epithelial cells, cisplatin significantly promoted the expression and activation of caspase-11. Inhibition of caspase-11 by small-interference RNA reduced cisplatin-induced cell apoptosis. Overexpression of caspase-11 promoted cell apoptosis by activating the caspase-3-related cell apoptosis. Furthermore, coimmunoprecipitation results showed there was a direct interaction between caspase-11 and caspase-3, and the interaction was enhanced by cisplatin. The fluorescence confocal microscopy results showed that caspase-11 and caspase-3 were colocalized in the cytoplasm of renal tubular epithelial cells. These results demonstrate that caspase-11 plays an important role in cisplatin-induced renal tubular injury. Caspase-11 promotes renal epithelial cell apoptosis by activating the caspase-3-dependent apoptotic pathway. Caspase-11 might be a potential target for therapeutic treatment against cisplatin-induced nephrotoxicity.
肾管状损伤是顺铂诱导肾毒性的标志。半胱氨酸蛋白酶-11（Caspase-11）是半胱氨酸蛋白酶家族的成员，在炎症和细胞死亡中发挥重要作用。然而，其在顺铂诱导的肾小管损伤中的作用尚不清楚。在顺铂处理的小鼠中，Caspase-11 的表达显著升高，并且 Caspase-11 的表达主要位于肾小管中。通过小干扰 RNA 或其抑制剂 Wedelolactone 抑制 Caspase-11 可减轻顺铂诱导的肾功能障碍和肾小管损伤。在培养的原代肾小管上皮细胞中，顺铂显著促进 Caspase-11 的表达和激活。通过小干扰 RNA 抑制 Caspase-11 可减少顺铂诱导的细胞凋亡。过表达 Caspase-11 通过激活 caspase-3 相关的细胞凋亡途径促进细胞凋亡。此外，共免疫沉淀结果表明 Caspase-11 和 Caspase-3 之间存在直接相互作用，并且这种相互作用通过顺铂增强。荧光共聚焦显微镜结果显示 Caspase-11 和 Caspase-3 在肾小管上皮细胞的细胞质中共定位。这些结果表明 Caspase-11 在顺铂诱导的肾小管损伤中起重要作用。Caspase-11 通过激活 caspase-3 依赖性凋亡途径促进肾上皮细胞凋亡。Caspase-11 可能是治疗顺铂诱导的肾毒性的潜在靶点。
