Abstract：
Fumonisin B1 (FB1), one of the most widely distributed mycotoxins found in grains and feeds as contaminants, affects many organs including the kidney once ingested. However, the nephrotoxicity of FB1 remains to be further uncovered. The connection between necroptosis and nephrotoxicity of FB1 has been investigated in this study. The results showed that mice exposed to high doses of FB1 (2.25 mg/kg b.w.) developed kidney damage, with significant increases in proinflammatory cytokines (Il-6, Il-1β), kidney injury-related markers (Ngal, Ntn-1), and gene expressions linked to necroptosis (Ripk1, Ripk3, Mlkl). The concentration-dependent damage effects of FB1 on PK-15 cells contain cytotoxicity, cellular inflammatory response, and necroptosis. These FB1-induced effects can be neutralized by pretreatment with the necroptosis inhibitor Nec-1. Additionally, FB1 caused mitochondrial damage and mitophagy in vivo and in vitro, whereas Mdivi-1, a mitophagy inhibitor, prevented these effects on PK-15 cells as well as, more crucially, necroptosis. In conclusion, the RIPK1/RIPK3/MLKL signal route of necroptosis, which may be controlled by mitophagy, mediated nephrotoxicity of FB1. Our findings clarify the underlying molecular pathways of FB1-induced nephrotoxicity.
摘要：
伏马菌素B1(FB1),作为污染物在谷物和饲料中分布最广泛的霉菌毒素之一，一旦摄入会影响包括肾脏在内的许多器官。然而,FB1的肾毒性还有待进一步发现.在这项研究中，已经研究了FB1的坏死与肾毒性之间的联系。结果表明，暴露于高剂量FB1（2.25mg/kgb.w.）的小鼠出现肾脏损害，随着促炎细胞因子（IL-6，IL-1β）的显着增加，肾损伤相关标志物(Ngal，Ntn-1),和与坏死相关的基因表达(Ripk1、Ripk3、Mlkl)。FB1对PK-15细胞的浓度依赖性损伤效应包含细胞毒性,细胞炎症反应，和坏死。这些FB1诱导的作用可以通过用坏死凋亡抑制剂Nec-1预处理来中和。此外,FB1在体内和体外引起线粒体损伤和线粒体自噬，而Mdivi-1，一种线粒体自噬抑制剂，阻止了这些对PK-15细胞的影响，更关键的是,坏死。总之,坏死的RIPK1/RIPK3/MLKL信号通路，这可能是由线粒体自噬控制的，FB1介导的肾毒性。我们的发现阐明了FB1诱导的肾毒性的潜在分子途径。
