{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T01:29:06Z","timestamp":1780968546049,"version":"3.54.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Copper overload is an established cause of nephrotoxicity, but the precise molecular mechanism remains unknown. Our study aimed to investigate the molecular mechanism of copper sulfate (CuSO<jats:sub>4<\/jats:sub>)-induced nephrotoxicity and the protective effect of the natural compound quercetin using a mouse model. Mice were orally administered CuSO<jats:sub>4<\/jats:sub> only (200 mg\/kg per day), or co-administered CuSO<jats:sub>4<\/jats:sub> (200 mg\/kg per day) plus quercetin (25, 50, or 100 mg\/kg per day), or quercetin only (100 mg\/kg per day), or vehicle for 28 days. The blood and kidneys were collected for the examination of serum biomarkers, oxidative stress biomarkers, changes in histopathology and gene and protein expression. Our results show that quercetin supplementation attenuates CuSO<jats:sub>4<\/jats:sub>-induced renal dysfunction and tubular necrosis in a dose-dependent manner. Quercetin supplementation at 50 and 100 mg\/kg significantly attenuated CuSO<jats:sub>4<\/jats:sub>-induced oxidative damage. Quercetin supplementation also inhibited the activities of caspases-9 and\u22123, and the expression of p53 and Bax mRNAs. Furthermore, quercetin supplementation markedly activated the expression of Nrf2 and HO-1 mRNAs, but inhibited the expression of NF-\u03baB, IL-1\u03b2, IL-6, and TNF-\u03b1 mRNAs. In conclusion, our results revealed that quercetin supplementation could inhibit CuSO<jats:sub>4<\/jats:sub>-induced nephrotoxicity in mice via the inhibition of mitochondrial apoptotic and NF-\u03baB pathways and the activation of Nrf2\/HO-1 pathway. Our study highlights quercetin as a potential candidate in treating copper overload-induced nephrotoxicity.<\/jats:p>","DOI":"10.3389\/fvets.2020.586033","type":"journal-article","created":{"date-parts":[[2021,1,9]],"date-time":"2021-01-09T05:57:47Z","timestamp":1610171867000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice"],"prefix":"10.3389","volume":"7","author":[{"given":"Xinyan","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongshan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhajit","family":"Das Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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 Chem Bio."},{"key":"B2","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.etap.2013.11.014","article-title":"Ecotoxicological effects of a veterinary food additive, copper sulphate, on antioxidant enzymes and mRNA expression in earthworms","volume":"37","author":"Xiong","year":"2014","journal-title":"Environ Toxicol Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.taap.2008.01.005","article-title":"Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy","volume":"229","author":"Viquez","year":"2008","journal-title":"Toxicol Appl Pharmacol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.taap.2016.01.007","article-title":"Relationship of antioxidant and oxidative stress markers in different organs following copper toxicity in a rat model","volume":"293","author":"Kumar","year":"2016","journal-title":"Toxicol Appl Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s10534-016-9942-4","article-title":"The neurotoxicity of iron, copper and cobalt in Parkinson's disease through ROS-mediated mechanisms","volume":"29","author":"Lan","year":"2016","journal-title":"Biometals"},{"key":"B6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1007\/s12011-016-0675-6","article-title":"Copper-induced spermatozoa head malformation is related to oxidative damage to testes in CD-1 mice","volume":"173","author":"Zhang","year":"2016","journal-title":"Biol Trace Elem Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/978-3-319-60189-2_16","article-title":"Neurotoxicity of copper","volume":"18","author":"Bulcke","year":"2017","journal-title":"Adv Neurobiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.intimp.2018.04.038","article-title":"Copper and arsenic-induced oxidative stress and immune imbalance are associated with activation of heat shock proteins in chicken intestines","volume":"60","author":"Wang","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"110236","DOI":"10.1016\/j.ecoenv.2020.110236","article-title":"Copper sulfate-induced endoplasmic reticulum stress promotes hepatic apoptosis by activating CHOP, JNK and caspase-12 signaling pathways","volume":"191","author":"Wu","year":"2020","journal-title":"Ecotoxicol Environ Saf"},{"key":"B10","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.yrtph.2016.09.025","article-title":"Temporal kinetics of organ damage in copper toxicity: a histopathological correlation in rat model","volume":"81","author":"Kumar","year":"2016","journal-title":"Regul Toxicol Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1007\/s10072-019-03942-z","article-title":"Brain volume is related to neurological impairment and to copper overload in Wilson's disease","volume":"40","author":"Smolinski","year":"2019","journal-title":"Neurol Sci"},{"key":"B12","first-page":"543","article-title":"Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. 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