College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China.
College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China.
Biomolecules. 2020 Jul 8;10(7):1010. doi: 10.3390/biom10071010.
The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO)-induced nephrotoxicity. Mice were treated with CuSO at 50, 100, 200 mg/kg/day or co-treated with CuSO (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO (400 μM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO exposure up-regulated the activities and mRNA expression of caspases-9 and -3 as well as the expression of glucose-regulated protein 78 (GRP78), GRP94, DNA damage-inducible gene 153 (GADD153/CHOP), caspase-12 mRNAs in the kidney tissues. Furthermore, superoxide dismutase and catalase pre-treatments partly inhibited CuSO-induced cytotoxicity by decreasing reactive oxygen species (ROS) production, activities of caspases-9 and -3 and DNA fragmentations in HEK293 cells. 4-PBA co-treatment significantly improved CuSO-induced cytotoxicity in HEK293 cells and inhibited CuSO exposure-induced renal dysfunction and pathology damage in the kidney tissues. In conclusion, our results reveal that oxidative stress and endoplasmic reticulum stress contribute to CuSO-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity.
铜暴露引起肾毒性的确切发病机制尚不清楚。本研究探讨了硫酸铜（CuSO）诱导肾毒性的潜在分子机制。小鼠用 CuSO 以 50、100、200 mg/kg/天或与 CuSO（200 mg/kg/天）和 4-苯丁酸（4-PBA，100 mg/kg/天）联合处理 28 天。用 CuSO（400 μM）处理 HEK293 细胞，或用超氧化物歧化酶、过氧化氢酶或 4-PBA 预处理 24 小时。结果表明，CuSO 暴露可导致小鼠肾脏组织肾功能障碍和肾小管坏死。CuSO 暴露上调了胱天蛋白酶-9 和 -3 的活性和 mRNA 表达以及葡萄糖调节蛋白 78（GRP78）、GRP94、DNA 损伤诱导基因 153（GADD153/CHOP）、胱天蛋白酶-12 的 mRNA 表达。此外，超氧化物歧化酶和过氧化氢酶预处理通过减少活性氧（ROS）产生、胱天蛋白酶-9 和 -3 的活性和 HEK293 细胞中的 DNA 片段化，部分抑制了 CuSO 诱导的细胞毒性。4-PBA 联合处理显著改善了 HEK293 细胞中 CuSO 诱导的细胞毒性，并抑制了 CuSO 暴露诱导的肾脏组织中肾功能障碍和病理损伤。总之，我们的结果表明氧化应激和内质网应激导致 CuSO 诱导的肾毒性。我们的研究强调，靶向内质网和氧化应激可能为铜过载引起的肾毒性提供一种治疗方法。
