Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways
The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO<sub>4</sub>)-induced nephrotoxicity. Mice were treated with CuSO<sub>4</sub> at 50, 100, 200 mg/kg/day or c...
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MDPI AG
2020-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/7/1010 |
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| author | Chongshan Dai Qiangqiang Liu Daowen Li Gaurav Sharma Jianli Xiong Xilong Xiao |
| author_facet | Chongshan Dai Qiangqiang Liu Daowen Li Gaurav Sharma Jianli Xiong Xilong Xiao |
| author_sort | Chongshan Dai |
| collection | DOAJ |
| description | The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO<sub>4</sub>)-induced nephrotoxicity. Mice were treated with CuSO<sub>4</sub> at 50, 100, 200 mg/kg/day or co-treated with CuSO<sub>4</sub> (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO<sub>4</sub> (400 μM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO<sub>4</sub> exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO<sub>4</sub> 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<sub>4</sub>-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<sub>4</sub>-induced cytotoxicity in HEK293 cells and inhibited CuSO<sub>4</sub> 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<sub>4</sub>-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity. |
| first_indexed | 2024-03-10T18:36:14Z |
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| language | English |
| last_indexed | 2024-03-10T18:36:14Z |
| publishDate | 2020-07-01 |
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| series | Biomolecules |
| spelling | doaj.art-14b2fe721fe6489f9f30141d37bccb6f2023-11-20T06:10:24ZengMDPI AGBiomolecules2218-273X2020-07-01107101010.3390/biom10071010Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress PathwaysChongshan Dai0Qiangqiang Liu1Daowen Li2Gaurav Sharma3Jianli Xiong4Xilong Xiao5College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaAdvanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACollege of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaThe precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO<sub>4</sub>)-induced nephrotoxicity. Mice were treated with CuSO<sub>4</sub> at 50, 100, 200 mg/kg/day or co-treated with CuSO<sub>4</sub> (200 mg/kg/day) and 4-phenylbutyric acid (4-PBA, 100 mg/kg/day) for 28 consecutive days. HEK293 cells were treated with CuSO<sub>4</sub> (400 μM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO<sub>4</sub> exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO<sub>4</sub> 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<sub>4</sub>-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<sub>4</sub>-induced cytotoxicity in HEK293 cells and inhibited CuSO<sub>4</sub> 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<sub>4</sub>-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity.https://www.mdpi.com/2218-273X/10/7/1010copperoxidative stressapoptosisendoplasmic reticulum stresskidneycytotoxicity |
| spellingShingle | Chongshan Dai Qiangqiang Liu Daowen Li Gaurav Sharma Jianli Xiong Xilong Xiao Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways Biomolecules copper oxidative stress apoptosis endoplasmic reticulum stress kidney cytotoxicity |
| title | Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways |
| title_full | Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways |
| title_fullStr | Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways |
| title_full_unstemmed | Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways |
| title_short | Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways |
| title_sort | molecular insights of copper sulfate exposure induced nephrotoxicity involvement of oxidative and endoplasmic reticulum stress pathways |
| topic | copper oxidative stress apoptosis endoplasmic reticulum stress kidney cytotoxicity |
| url | https://www.mdpi.com/2218-273X/10/7/1010 |
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