title: A Role for Tubular Necroptosis in Cisplatin-Induced AKI.
abstract: Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway-receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)-by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-α, TNF-related weak inducer of apoptosis, and IFN-γ) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI.
authors: Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China; Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing, China;
authors: Yanfang
authors: Y
authors: Xu
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Huabin
authors: H
authors: Ma
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Jing
authors: J
authors: Shao
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Jianfeng
authors: J
authors: Wu
authors: Department of Pathology, Fujian Medical University, Fuzhou, China; and.
authors: Linying
authors: L
authors: Zhou
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Zhirong
authors: Z
authors: Zhang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Yuze
authors: Y
authors: Wang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Zhe
authors: Z
authors: Huang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;
authors: Junming
authors: J
authors: Ren
authors: Department of Internal Medicine, First Affiliated Hospital, Xiamen University, Xiamen, China.
authors: Suhuan
authors: S
authors: Liu
authors: Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing, China;
authors: Xiangmei
authors: X
authors: Chen
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China; jhan@xmu.edu.cn jhan@scripps.edu.
authors: Jiahuai
authors: J
authors: Han
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis / Q000139:chemically induced; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D002945:Cisplatin
keywords: cisplatin nephrotoxicity; necroptosis; renal proximal tubule cell