Yang Xuan, Liu Sheng, Huang Chuchu, Wang Haomiao, Luo Yunbo, Xu Wentao, Huang Kunlun
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China.
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China; Beijing Laboratory for Food Quality and Safety, Beijing, 100083, China.
Toxicology. 2017 May 1;382:75-83. doi: 10.1016/j.tox.2017.03.009. Epub 2017 Mar 9.
Ochratoxin A (OTA) has many nephrotoxic effects and is a promising compound for the study of nephrotoxicity. Human renal proximal tubular cells (HKC) are an important model for the study of renal reabsorption, renal physiology and pathology. Since the induction of OTA in renal senescence is largely unknown, whether OTA can induce renal senescence, especially at a sublethal dose, and the mechanism of OTA toxicity remain unclear. In our study, a sublethal dose of OTA led to an enhanced senescent phenotype, β-galactosidase staining and senescence associated secretory phenotype (SASP). Cell cycle arrest and cell shape alternations also confirmed senescence. In addition, telomere analysis by RT-qPCR allowed us to classify OTA-induced senescence as a premature senescence. Western blot assays showed that the p53-p21 and the p16-pRB pathways and the ezrin-associated cell spreading changes were activated during the OTA-induced senescence of HKC. In conclusion, our results demonstrate that OTA promotes the senescence of HKC through the p53-p21 and p16-pRB pathways. The understanding of the mechanisms of OTA-induced senescence is critical in determining the role of OTA in cytotoxicity and its potential carcinogenicity.
赭曲霉毒素A（OTA）具有多种肾毒性作用，是研究肾毒性的一种有前景的化合物。人肾近端小管细胞（HKC）是研究肾脏重吸收、肾脏生理学和病理学的重要模型。由于OTA在肾脏衰老中的诱导作用在很大程度上尚不清楚，OTA是否能诱导肾脏衰老，尤其是在亚致死剂量下，以及OTA毒性的机制仍不明确。在我们的研究中，亚致死剂量的OTA导致衰老表型增强、β-半乳糖苷酶染色和衰老相关分泌表型（SASP）。细胞周期停滞和细胞形态改变也证实了衰老。此外，通过RT-qPCR进行的端粒分析使我们能够将OTA诱导的衰老归类为早衰。蛋白质免疫印迹分析表明，在HKC的OTA诱导衰老过程中，p53-p21和p16-pRB通路以及与埃兹蛋白相关的细胞铺展变化被激活。总之，我们的结果表明，OTA通过p53-p21和p16-pRB通路促进HKC的衰老。了解OTA诱导衰老的机制对于确定OTA在细胞毒性及其潜在致癌性中的作用至关重要。
