Department of Food Nutrition and Safety, Dalian Medical University, No. 9W. Lushun South Road, Dalian 116044, China.
Department of Cardiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
J Agric Food Chem. 2022 May 25;70(20):6213-6223. doi: 10.1021/acs.jafc.1c08349. Epub 2022 May 11.
Patulin (PAT) is a common mycotoxin, widely found in cereals, seafood, nuts, and especially in fruits and their products. Exposure to this mycotoxin has been reported to induce kidney injury. However, the possible mechanism remains unclear. In our study, short-term high-dose intake of PAT caused acute kidney injury (AKI) in mice. We performed high-throughput transcriptional sequencing to identify differentially expressed genes (DEGs) between the treatment and control groups. The ferroptosis signaling pathway had the highest enrichment, suggesting ferroptosis is involved in PAT-induced AKI. Further, the existence of ferroptosis and autophagy was confirmed by observing the changes of mitochondria morphology and the formation of autophagosomes by electron microscopy. And the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), p62, nuclear receptor coactivator 4 (NCOA4), and ferritin heavy chain 1 (FTH1) were downregulated, whereas acyl-CoA synthase long-chain family member 4 (ACSL4), transferrin (TF), LC3, and ferritin light chain (FTL) expression were upregulated in PAT-exposed mice. These results suggested autophagy-dependent ferroptosis occurred in the animal model. This view has also been confirmed in the human renal tubular epithelial cell (HKC) experiments. Autophagy inhibitor 3-methyladenine (3MA) attenuated PAT-induced ferroptosis and the iron contents in HKC cells. Simultaneous autophagy-dependent ferroptosis can be inhibited by ferroptosis inhibitors ferrostatin-1 (Fer-1) and desferrioxamine (DFO). In general, this study provides a new perspective for exploring the new mechanism of acute kidney injury caused by PAT.
棒曲霉素（PAT）是一种常见的真菌毒素，广泛存在于谷物、海鲜、坚果中，尤其存在于水果及其制品中。据报道，暴露于该真菌毒素会导致肾脏损伤。然而，其可能的机制尚不清楚。在我们的研究中，短期高剂量摄入 PAT 可导致小鼠急性肾损伤（AKI）。我们进行了高通量转录测序，以鉴定处理组和对照组之间差异表达的基因（DEGs）。铁死亡信号通路的富集度最高，表明铁死亡参与了 PAT 诱导的 AKI。此外，通过观察电镜下线粒体形态的变化和自噬体的形成，进一步证实了铁死亡和自噬的存在。并且溶质载体家族 7 成员 11（SLC7A11）、谷胱甘肽过氧化物酶 4（GPX4）、p62、核受体共激活因子 4（NCOA4）和铁蛋白重链 1（FTH1）的表达下调，而酰基辅酶 A 合成酶长链家族成员 4（ACSL4）、转铁蛋白（TF）、LC3 和铁蛋白轻链（FTL）的表达上调。这些结果表明，自噬依赖性铁死亡发生在动物模型中。这一观点在人肾小管上皮细胞（HKC）实验中也得到了证实。自噬抑制剂 3-甲基腺嘌呤（3MA）可减轻 PAT 诱导的铁死亡和 HKC 细胞中的铁含量。同时，铁死亡抑制剂 ferrostatin-1（Fer-1）和去铁胺（DFO）可抑制依赖自噬的铁死亡。总之，本研究为探索 PAT 引起的急性肾损伤的新机制提供了新视角。
