Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Intensive Care Medicine, Third Affiliated Hospital (Daping Hospital), Army Medical University (Third Military Medical University), Chongqing 400042, China.
Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
Int Immunopharmacol. 2020 Dec;89(Pt A):106999. doi: 10.1016/j.intimp.2020.106999. Epub 2020 Oct 9.
Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTβR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells apoptosis. While blocking LIGHT with the soluble fusion protein LTβR-Ig or HVEM-Ig accelerated the HK-2 cells apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial apoptosis pathways.
顺铂被广泛用作治疗实体瘤患者的化疗药物。顺铂治疗的最常见副作用是肾毒性。最近的研究表明，线粒体凋亡途径参与了顺铂诱导的急性肾损伤（Cis-AKI）。LIGHT 是肿瘤坏死因子超家族（TNFSF14）的第 14 个成员，被发现可诱导某些类型的肿瘤细胞凋亡。到目前为止，尚未有 LIGHT 与 Cis-AKI 之间的联系的报道。在这项研究中，我们观察到顺铂处理后小鼠肾脏组织中 LIGHT 及其受体 HVEM 和 LTβR 的表达增加。LIGHT 缺乏加重了肾损伤，表现为更严重的肾小管损伤；血清肌酐（Scr）、血尿素氮（BUN）以及肾损伤分子-1（KIM-1）和炎症细胞因子 mRNA 在肾组织中的水平显著升高。此外，在 LIGHT KO 小鼠的肾脏组织中，顺铂诱导的线粒体损伤以及促凋亡分子 Bax、细胞色素 C（Cyt C）、裂解的 caspase-3 和裂解的 caspase-9 的水平显著增加；相反，抗凋亡分子 Bcl-2 的表达明显减少，与 WT 小鼠相比，表明 LIGHT 缺乏加速了这些小鼠肾近端小管细胞中顺铂诱导的线粒体凋亡。因此，重组人 LIGHT（rLIGHT）的治疗显示可减轻体内顺铂引起的肾损伤。在人肾小管上皮细胞系 HK-2 细胞暴露于 rLIGHT 刺激后观察到类似的结果，这表现为线粒体功能障碍（通过氧化应激和膜电位变化的显著减少来证实）的减少以及细胞凋亡的百分比减少。而用可溶性融合蛋白 LTβR-Ig 或 HVEM-Ig 阻断 LIGHT 则加速了 HK-2 细胞的凋亡。总之，LIGHT 缺乏通过促进线粒体凋亡途径加重 Cis-AKI。
