累积数据证实，甲氨蝶呤（MTX），一种著名的免疫抑制和抗癌药物，会导致肾毒性。肿瘤坏死因子α（TNF-α）的抑制剂英夫利塞（INF）已被证明具有抗炎特性。因此，本研究旨在通过研究其干扰不同死亡途径、氧化应激以及线粒体生物发生等可能的分子机制，探讨INF对MTX诱导的大鼠肾毒性的潜在肾保护作用。大鼠在单次20mg/kg MTX注射前72小时接受7mg/kg INF腹腔注射。MTX肾毒性表现为明显增加的血清尿素和肌酸酐水平，以及肾脏炎症标志物TNF-α和白细胞介素-6（IL-6）以及肾脏氧化应激标志物丙二醛（MDA）的增加，而与对照组相比，肾脏抗氧化酶超氧化物歧化酶（SOD）显著降低。INF注射前给予MTX显著逆转了这些MTX诱导的效应。此外，MTX影响了线粒体生物发生，而INF减轻了这种影响，如过氧化物酶活化受体γ共活化因子-1α（PGC-1α）的表达增加所示。最后，MTX在肾组织中触发了凋亡和自噬级联反应，即通过减少抗凋亡蛋白Bcl-2的表达以及升高促凋亡蛋白Bax和自噬的关键调节因子beclin-1和LC-3的表达，而INF预处理则对抗了MTX的这些凋亡和自噬效应。总之，这些结果表明INF能够提供对抗MTX诱导的肾毒性的保护作用，这可以通过其抗氧化、抗炎、抗凋亡、抗自噬作用以及上调线粒体生物发生来解释。© 2023. 作者。

Accumulating data confirms that Methotrexate (MTX), a well-known immunosuppressive and anticancer drug, causes nephrotoxicity. Infliximab (INF), the inhibitor of tumor necrosis factor-alpha (TNF-α), was proven to have anti-inflammatory properties. Thus, it may have potential in preventing MTX-induced nephrotoxicity. Therefore, this study aimed to inspect the prospective nephroprotective effect of INF on MTX-induced rat nephrotoxicity through investigating the possible molecular mechanisms, including its interference with different death routes, oxidative stress as well as mitochondrial biogenesis. Rats received an INF intraperitoneal single dose of 7 mg/kg 72 h prior to a single 20 mg/kg MTX injection. MTX nephrotoxicity was demonstrated by significantly increased serum levels of the renal indicators urea and creatinine as well as renal inflammatory markers TNF-α and Interleukin-6 (IL-6) and the renal oxidative stress marker malondialdehyde (MDA), while renal antioxidant enzyme superoxide dismutase (SOD) was significantly decreased compared to control. INF injection prior to MTX markedly reversed these MTX-induced effects. Besides, MTX impaired mitochondrial biogenesis, while INF attenuated this impairment, as indicated by increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Finally, MTX triggered apoptotic and autophagic cascades in renal tissues as evidenced by reduced anti-apoptotic Bcl-2 protein expression as well as elevated expression of the pro-apoptotic protein Bax and both key regulators of autophagy; beclin-1 and LC-3, whereas INF pretreatment counteracted these apoptotic and autophagic effects of MTX. Summarily, these results suggest that INF provides protection against MTX-induced nephrotoxicity which could be elucidated by its antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagic effects as well as upregulating mitochondrial biogenesis.© 2023. The Author(s).