Qiao Na, Yang Yanyang, Liao Jianzhao, Zhang Hui, Yang Fan, Ma Feiyang, Han Qingyue, Yu Wenlan, Li Ying, Hu Lianmei, Pan Jiaqiang, Hussain Riaz, Tang Zhaoxin
College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China.
Ecotoxicol Environ Saf. 2021 May 1;218:112284. doi: 10.1016/j.ecoenv.2021.112284.
Copper poses huge environmental and public health concerns due to its widespread and persistent use in the past several decades. Although it is well established that at higher levels copper causes nephrotoxicity, the exact mechanisms of its toxicity is not fully understood. Therefore, this experimental study for the first time investigates the potential molecular mechanisms including transcriptomics, metabolomics, serum biochemical, histopathological, cell apoptosis and autophagy in copper-induced renal toxicity in pigs. A total of 14 piglets were randomly assigned to two group (7 piglets per group) and treated with a standard diet (11 mg CuSO per kg of feed) and a high copper diet (250 mg CuSO per kg of feed). The results of serum biochemical tests and renal histopathology suggested that 250 mg/kg CuSO in the diet significantly increased serum creatinine (CREA) and induced renal tubular epithelial cell swelling. Results on transcriptomics and metabolomics showed alteration in 804 genes and 53 metabolites in kidneys of treated pigs, respectively. Combined analysis of transcriptomics and metabolomics indicated that different genes and metabolism pathways in kidneys of treated pigs were involved in glycerophospholipids metabolism and glycosphingolipid metabolism. Furthermore, copper induced mitochondrial apoptosis characterized by increased bax, bak, caspase 3, caspase 8 and caspase 9 expressions while decreased bcl-xl and bcl2/bax expression. Exposure to copper decreased the autophagic flux in terms of increased number of autophagosomes, beclin1 and LC3b/LC3a expression and p62 accumulation. These results indicated that the imbalance of glycosphingolipid metabolism, the impairment of autophagy and increase mitochondrial apoptosis play an important role in copper induced renal damage and are useful mechanisms to understand the mechanisms of copper nephrotoxicity.
由于在过去几十年中铜的广泛和持续使用，它引起了巨大的环境和公共卫生问题。虽然已经明确，在较高水平时铜会导致肾毒性，但其毒性的确切机制尚未完全了解。因此，本实验研究首次调查了猪铜诱导肾毒性中包括转录组学、代谢组学、血清生化、组织病理学、细胞凋亡和自噬在内的潜在分子机制。总共14只仔猪被随机分为两组（每组7只仔猪），分别用标准饮食（每千克饲料含11毫克硫酸铜）和高铜饮食（每千克饲料含250毫克硫酸铜）进行处理。血清生化测试和肾脏组织病理学结果表明，饮食中250毫克/千克的硫酸铜显著增加了血清肌酐（CREA）并诱导肾小管上皮细胞肿胀。转录组学和代谢组学结果分别显示，处理后猪肾脏中有804个基因和53种代谢物发生了改变。转录组学和代谢组学的联合分析表明，处理后猪肾脏中的不同基因和代谢途径参与了甘油磷脂代谢和糖鞘脂代谢。此外，铜诱导线粒体凋亡，其特征是bax、bak、caspase 3、caspase 8和caspase 9表达增加，而bcl-xl和bcl2/bax表达降低。铜暴露导致自噬通量降低，表现为自噬体数量增加、beclin1和LC3b/LC3a表达增加以及p62积累。这些结果表明，糖鞘脂代谢失衡、自噬受损和线粒体凋亡增加在铜诱导的肾损伤中起重要作用，并且是理解铜肾毒性机制的有用机制。
