{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:50:22Z","timestamp":1787579422479,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Projects in Chinese National Science and Technology Pillar Program during the 12th Five-year Plan Period","award":["2015BAD11B03"],"award-info":[{"award-number":["2015BAD11B03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The precise pathogenic mechanism in Cu exposure-cause nephrotoxicity remains unclear. This study investigated the underlying molecular mechanism of copper sulfate (CuSO4)-induced nephrotoxicity. Mice were treated with CuSO4 at 50, 100, 200 mg\/kg\/day or co-treated with CuSO4 (200 mg\/kg\/day) and 4-phenylbutyric acid (4-PBA, 100 mg\/kg\/day) for 28 consecutive days. HEK293 cells were treated with CuSO4 (400 \u03bcM) with or without superoxide dismutase, catalase or 4-PBA for 24 h. Results showed that CuSO4 exposure can cause renal dysfunction and tubular necrosis in the kidney tissues of mice. CuSO4 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 CuSO4-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 CuSO4-induced cytotoxicity in HEK293 cells and inhibited CuSO4 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 CuSO4-induced nephrotoxicity. Our study highlights that targeting endoplasmic reticulum and oxidative stress may offer an approach for Cu overload-caused nephrotoxicity.<\/jats:p>","DOI":"10.3390\/biom10071010","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:25:28Z","timestamp":1594373128000},"page":"1010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Molecular Insights of Copper Sulfate Exposure-Induced Nephrotoxicity: Involvement of Oxidative and Endoplasmic Reticulum Stress Pathways"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4677-0524","authenticated-orcid":false,"given":"Chongshan","family":"Dai","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"},{"name":"College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daowen","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1754-7163","authenticated-orcid":false,"given":"Gaurav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-6026","authenticated-orcid":false,"given":"Jianli","family":"Xiong","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilong","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/nchembio.72","article-title":"Mechanisms for copper acquisition, distribution and regulation","volume":"4","author":"Kim","year":"2008","journal-title":"Nat. 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