title: Saikosaponin-D reduces cisplatin-induced nephrotoxicity by repressing ROS-mediated activation of MAPK and NF-κB signalling pathways.
abstract: The nephrotoxicity induced by cisplatin (DDP) severely limits the clinical efficacy of this widely used anticancer agent. The observed nephrotoxicity may be the result of DDP-induced inflammation and apoptosis. Saikosaponin-D (SSD), a triterpenoid saponin, has numerous pharmacological properties. The goal of the present study was to investigate whether and how SSD protected against DDP-induced nephrotoxicity. Non-cytotoxic levels of SSD significantly increased the viability rate, improved the nuclear morphology, and attenuated the caspase-3 activation and programmed apoptosis of DDP-treated HK-2 cells. In addition, SSD treatment markedly inhibited the release of tumour necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the production of nitric oxide and the expression of inducible nitric oxide synthase (iNOS) by these cells. More importantly, SSD effectively blocked the DDP-induced activation of NF-κB, P38, JNK, and MAPKs. Furthermore, we found that U0126 (a specific inhibitor of MAPKs) strongly inhibited the IKK/IκB/NF-κB-dependent release of pro-inflammatory cytokines and iNOS gene expression. Finally, we demonstrated that SSD decreased the level of reactive oxygen species (ROS) accumulation and that the specific ROS scavenger N-acetylcysteine (NAC) markedly inhibited the DDP-induced activation of MAPK and phosphorylation of the downstream signal NF-κB, which in turn reduced the levels of pro-inflammatory cytokine release and iNOS gene expression. Our results suggest that the SSD-mediated alleviation of DDP-induced nephrotoxicity was due to uncoupling of the ROS, P38, and JNK/NF-κB signalling pathways.
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Oncology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Chengxue
authors.initials: C
authors.lastname: Dang
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710000, PR China. Electronic address: huiwentaoedu@163.com.
authors.forename: Wentao
authors.initials: W
authors.lastname: Hui
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012503:Saponins; D009569:Nitric Oxide; D009828:Oleanolic Acid; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin; C025759:saikosaponin D
keywords: Cisplatin nephrotoxicity; MAPKs; NF-κB; ROS; Saikosaponin-D