School of Public Health, Zunyi Medical University, No.1 Campus Road, Xinpu District, Zunyi, 563000, Guizhou, People's Republic of China.
Key Laboratory of Maternal & Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi, 563000, Guizhou, People's Republic of China.
Arch Toxicol. 2024 Oct;98(10):3323-3336. doi: 10.1007/s00204-024-03805-3. Epub 2024 Jun 19.
Ochratoxin A (OTA), a secondary fungal metabolite known for its nephrotoxic effects, is prevalent in various feeds and food items. Our recent study suggests that OTA-induced nephrotoxicity is linked to the Sigma-1 receptor (Sig-1R)-mediated mitochondrial pathway apoptosis in human proximal tubule epithelial-originated kidney-2 (HK-2) cells. However, the contribution of Sig-1R to OTA-induced nephrotoxicity involving other forms of regulated cell death, such as ferroptosis, remains unexplored. In this investigation, cell viability, malondialdehyde (MDA) levels, glutathione (GSH) levels, and protein expressions in HK-2 cells treated with OTA and/or Ferrostatin-1/blarcamesine hydrochloride/BD1063 dihydrochloride were assessed. The results indicate that a 24 h-treatment with 1 μM OTA significantly induces ferroptosis by inhibiting Sig-1R, subsequently promoting nuclear receptor coactivator 4 (NCOA4), long-chain fatty acid-CoA ligase 4 (ACSL4), arachidonate 5-lipoxygenase (ALOX5), autophagy protein 5 (ATG5), and ATG7, inhibiting ferritin heavy chain (FTH1), solute carrier family 7 member 11 (SLC7A11/xCT), glutathione peroxidase 4 (GPX4), peroxiredoxin 6 (PRDX6), and ferroptosis suppressor protein 1 (FSP1), reducing GSH levels, and increasing MDA levels (P < 0.05). In conclusion, OTA induces ferroptosis by inhibiting Sig-1R, subsequently promoting ferritinophagy, inhibiting GPX4/FSP1 antioxidant systems, reducing GSH levels, and ultimately increasing lipid peroxidation levels in vitro.
赭曲霉毒素 A（OTA）是一种已知具有肾毒性的次级真菌代谢物，普遍存在于各种饲料和食品中。我们最近的研究表明，OTA 诱导的肾毒性与 Sigma-1 受体（Sig-1R）介导的人近端肾小管上皮源性肾-2（HK-2）细胞中线粒体途径细胞凋亡有关。然而，Sig-1R 对 OTA 诱导的涉及其他形式的受调控细胞死亡（如铁死亡）的肾毒性的贡献仍未被探索。在这项研究中，我们评估了 OTA 和/或 Ferrostatin-1/Blarcamesine Hydrochloride/BD1063 Dihydrochloride 处理的 HK-2 细胞中的细胞活力、丙二醛（MDA）水平、谷胱甘肽（GSH）水平和蛋白表达。结果表明，用 1 μM OTA 处理 24 小时会显著通过抑制 Sig-1R 诱导铁死亡，随后促进核受体共激活因子 4（NCOA4）、长链脂肪酸辅酶 A 连接酶 4（ACSL4）、花生四烯酸 5-脂氧合酶（ALOX5）、自噬蛋白 5（ATG5）和 ATG7，抑制铁蛋白重链（FTH1）、溶质载体家族 7 成员 11（SLC7A11/xCT）、谷胱甘肽过氧化物酶 4（GPX4）、过氧化物酶 6（PRDX6）和铁死亡抑制蛋白 1（FSP1），降低 GSH 水平，并增加 MDA 水平（P < 0.05）。总之，OTA 通过抑制 Sig-1R 诱导铁死亡，随后促进铁蛋白自噬，抑制 GPX4/FSP1 抗氧化系统，降低 GSH 水平，最终增加细胞内脂质过氧化水平。
