Yu Xiaowen, Yang Yunwen, Yuan Hui, Wu Meng, Li Shuzhen, Gong Wei, Yu Jing, Xia Weiwei, Zhang Yue, Ding Guixia, Huang Songming, Jia Zhanjun, Zhang Aihua
Department of Nephrology, Children's Hospital of Nanjing Medical UniversityNanjing 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical UniversityNanjing 210008, China.
Department of Nephrology, Children's Hospital of Nanjing Medical University Nanjing 210008, China.
Am J Transl Res. 2017 Mar 15;9(3):1222-1229. eCollection 2017.
Cisplatin is one of the most potent cytotoxic drug for the treatment of many types of cancer. However, the side effects on normal tissues, particularly on the kidney, greatly limited its use in clinic. Emerging evidence demonstrated that cisplatin could directly cause mesangial cell apoptosis, while the potential mechanism is still elusive. Here we examined the contribution of COX-2 in cisplatin-induced mesangial cell apoptosis. Firstly, we found cisplatin induced cell apoptosis in mesangial cells shown by increased number of apoptotic cells in parallel with the upregulation of Bax and the downregulation of Bcl-2. Interestingly, cisplatin-induced cell apoptosis was accompanied by an upregulation of COX-2 at both mRNA and protein levels in dose- and time-dependent manners. Importantly, inhibition of COX-2 via a specific COX-2 inhibitor celecoxib markedly blocked cisplatin-induced mesangial cell apoptosis as evidenced by the decreased number of apoptotic cells, blocked increments of cleaved caspase-3 and Bax, and reversed Bcl-2 downregulation. Meanwhile, cisplatin-induced PGE2 production was markedly blocked by the treatment of celecoxib. In conclusion, this study indicated that COX-2/PGE2 cascade activation mediated cisplatin-induced mesangial cell apoptosis. The findings not only offered new insights into the understanding of cisplatin nephrotoxicity but also provided the therapeutic potential by targeting COX-2/PGE2 cascade in treating cisplatin-induced kidney injury.
顺铂是治疗多种癌症最有效的细胞毒性药物之一。然而，其对正常组织尤其是肾脏的副作用极大地限制了它在临床上的应用。新出现的证据表明，顺铂可直接导致系膜细胞凋亡，但其潜在机制仍不清楚。在此，我们研究了COX-2在顺铂诱导的系膜细胞凋亡中的作用。首先，我们发现顺铂诱导系膜细胞凋亡，表现为凋亡细胞数量增加，同时Bax上调和Bcl-2下调。有趣的是，顺铂诱导的细胞凋亡伴随着COX-2在mRNA和蛋白水平上以剂量和时间依赖性方式上调。重要的是，通过特异性COX-2抑制剂塞来昔布抑制COX-2可显著阻断顺铂诱导的系膜细胞凋亡，这表现为凋亡细胞数量减少、裂解的caspase-3和Bax的增加被阻断以及Bcl-2下调被逆转。同时，塞来昔布治疗可显著阻断顺铂诱导的PGE2产生。总之，本研究表明COX-2/PGE2级联激活介导了顺铂诱导的系膜细胞凋亡。这些发现不仅为理解顺铂肾毒性提供了新的见解，也为通过靶向COX-2/PGE2级联治疗顺铂诱导的肾损伤提供了治疗潜力。
