Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, China.
Cell Death Dis. 2021 Feb 15;12(2):186. doi: 10.1038/s41419-021-03458-5.
Chemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.
化疗药物诱导的肾毒性限制了其在癌症治疗中的临床应用。细胞焦亡，一种新发现的程序性细胞死亡方式，最近被报道与肾脏疾病有关。然而，细胞焦亡在化疗药物诱导的肾毒性中的作用尚未完全阐明。在此，我们证明化疗药物顺铂或阿霉素以时间和浓度依赖的方式诱导培养的人肾小管上皮细胞中gasdermin E (GSDME)的裂解。形态上，顺铂或阿霉素处理的肾小管上皮细胞从细胞膜上出现大泡。此外，与 caspase 9 不同，caspase 3 的激活与顺铂或阿霉素处理的肾小管上皮细胞中 GSDME 的裂解有关。同时，沉默 GSDME 通过增加细胞活力和减少 LDH 释放，减轻顺铂或阿霉素诱导的 HK-2 细胞细胞焦亡。此外，用 Ac-DMLD-CMK 处理，一种针对小鼠 caspase 3-Gsdme 信号的多肽，可抑制 caspase 3 和 Gsdme 的激活，减轻肾功能恶化，减轻肾小管上皮细胞损伤，并减少体内炎症细胞因子的分泌。具体而言，GSDME 的裂解依赖于 ERK 和 JNK 信号。NAC，一种活性氧 (ROS) 抑制剂，通过 JNK 信号减少人肾小管上皮细胞中 GSDME 的裂解。因此，我们推测化疗药物诱导的肾小管上皮细胞细胞焦亡是通过 ROS-JNK-caspase 3-GSDME 信号介导的，这意味着针对 GSDME 的治疗方法可能在克服化疗药物诱导的肾毒性方面有效。
