A Role for Tubular Necroptosis in Cisplatin-Induced AKI
A Role for Tubular Necroptosis in Cisplatin-Induced AKI
复制标题
肾小管坏死性凋亡在顺铂诱发的 AKI 中的作用
DOI：
10.1681/asn.2014080741
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发表时间：
2015-11-01
影响因子：
13.6
通讯作者：
Han, Jiahuai
中科院分区：
文献类型：
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作者：
Xu, Yanfang;Ma, Huabin;Han, Jiahuai
近端小管中的细胞死亡和炎症是顺铂诱导的阿基的标志，但这些作用的机制尚未完全阐明。在这里，我们研究了坏死性凋亡（一种程序性坏死）是否在顺铂诱导的阿基中起作用。我们发现，通过基因敲除或化学抑制剂抑制坏死性凋亡途径受体相互作用蛋白1（RIP 1）、RIP 3或混合谱系激酶结构域样蛋白（MLKL）的任何核心组分，可减少顺铂诱导的小鼠近端小管损伤。在培养的近端肾小管细胞中获得了类似的结果。此外，培养细胞的坏死性凋亡可由顺铂或由细胞因子（TNF-α，TNF相关的细胞凋亡弱诱导剂和IFN-γ）的组合诱导，这些细胞因子在顺铂处理的小鼠的近端小管中上调。然而，顺铂诱导的RIP 1和RIP 3的表达在培养的肾小管细胞中的细胞因子释放的情况下增加。相应地，RIP 1或RIP 3的过表达在体外增强顺铂诱导的坏死性凋亡。值得注意的是，顺铂治疗的小鼠中的炎性细胞因子上调在R1 P3或MLKL缺陷小鼠中部分减少，表明涉及这些基因和炎性细胞因子的正反馈回路促进坏死性凋亡进展。因此，我们的数据表明，坏死性凋亡是顺铂诱导的肾毒性阿基中近端肾小管细胞死亡的主要机制。
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-alpha, TNF-related weak inducer of apoptosis, and IFN-gamma) 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 R1P3- 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.