Tim-3 deficiency aggravates cadmium nephrotoxicity via regulation of NF-κB signaling and mitochondrial damage
Tim-3 deficiency aggravates cadmium nephrotoxicity via regulation of NF-κB signaling and mitochondrial damage
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DOI：
10.1016/j.intimp.2023.111434
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发表时间：
2024-01-03
影响因子：
5.6
通讯作者：
Lou，Qiang
中科院分区：
文献类型：
--
作者：
Yin，Guanyi;Wang，Zhonghang;Lou，Qiang
肾脏是镉严重损伤的靶器官。镉暴露引起的肾脏损伤受炎症反应和线粒体损伤的影响很大。T细胞免疫球蛋白结构域和粘蛋白结构域3（Tim-3）是作为负性免疫检查点发挥功能以调节炎症反应的必需蛋白。以不同剂量（0、1.5、3、4.5mg/kg）和时间（0、3、5、7 d）的镉处理小鼠，以评估镉对肾损伤的影响。我们发现诱导小鼠肾损伤的最佳方法是腹腔注射4.5mg/kg的镉，连续5天。有趣的是，给小鼠静脉注射4.5毫克/公斤的镉，持续7天，大大降低了它们的存活率。镉暴露后，Tim-3基因敲除小鼠的尿素氮和肌酐的血液浓度高于对照小鼠。根据RNA-seq和实时RT-PCR数据，Tim-3影响氧化应激相关基因的表达，如UDP葡萄糖醛酸转移酶家族1成员A9（Ugt 1a 9），氧化应激诱导的生长抑制因子2（Osgin 2）和S100钙结合蛋白A8（S100 a8）。Tim-3缺陷还导致核因子-κ B（NF-κB）信号通路激活。NF-κB抑制剂2-[（氨基羰基）氨基]-5-（4-氟苯基）-3-噻吩甲酰胺（TPCA-1）显著减轻镉暴露的Tim-3基因敲除小鼠的细胞凋亡、氧化应激反应和肾小管炎症。此外，镉引起明显的B细胞淋巴瘤蛋白2（Bcl-2）相关的X（Bax）从细胞质易位到线粒体，这可以被TPCA-1抑制。总之，Tim-3防止线粒体损伤和NF-κB信号传导激活，从而提供针对镉肾毒性的保护。
Kidney is the target organ of serious cadmium injury. Kidney damage caused by cadmium exposure is greatly influenced by the inflammatory response and mitochondrial damage. T cell immunoglobulin domain and mucin domain 3 (Tim-3) is an essential protein that functions as a negative immunological checkpoint to regulate inflammatory responses. Mice were given cadmium treatments at various dosages (0, 1.5, 3, 4.5 mg/kg) and times (0, 3, 5, 7 days) to assess the effects of cadmium on kidney damage. We found that the optimal way to induce kidney injury in mice was to inject 4.5 mg/kg of cadmium intraperitoneally for five days. It is interesting that giving mice 4.5 mg/kg of cadmium intravenously for seven days drastically lowered their survival rate. After cadmium exposure, Tim-3 knockout mice exhibited higher blood concentrations of urea nitrogen and creatinine compared to control mice. Tim-3 impacted the expression of oxidative stress-associated genes such as UDP glucuronosyltransferase family 1 member A9 (Ugt1a9), oxidative stress-induced growth inhibitor 2 (Osgin2), and S100 calcium binding protein A8 (S100a8), according to RNA-seq and real-time RT-PCR data. Tim-3 deficiency also resulted in activated nuclear factor-kappa B (NF-κB) signaling pathway. The NF-κB inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) significantly alleviated cell apoptosis, oxidative stress response, and renal tubule inflammation in Tim-3 knockout mice exposed to cadmium. Furthermore, cadmium caused obvious B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) translocation from cytoplasm to mitochondria, which can be inhibited by TPCA-1. In conclusion, Tim-3 prevented mitochondrial damage and NF-κB signaling activation, hence providing protection against cadmium nephrotoxicity.