title: Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells.
abstract: Resveratrol has been reported to ameliorate Cd-induced nephrotoxicity. However, the beneficial effects of resveratrol on Cd-induced nephrotoxicity and the underlying mechanisms of this protection remain unclear. Here, we showed that mouse renal tubular epithelial (TCMK-1) cells exposed to Cd experienced significantly increased mitochondrial reactive oxygen species (mROS) production, as well as decreased mitochondrial biogenesis and function. Cd exposure dramatically decreased Sirt3 protein expression and activity and promoted the acetylation of forkhead box O3 (FoxO3a). Moreover, Cd exposure led to a decreased binding affinity of FoxO3a to the promoters of both peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and superoxide dismutase 2 (SOD2), powerful and broad regulators of mitochondrial biogenesis and mROS metabolism. Meanwhile, resveratrol remarkably reduced mROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of FoxO3a-mediated mitochondria gene expression of PGC-1α and SOD2. Importantly, mechanistic study revealed that ERK1/2 activation was associated with increased apoptosis induced by Cd, resveratrol suppressed Cd-induced apoptosis in mice kidney. Taken together, our data suggest a novel mechanism of action for resveratrol-attenuated Cd-induced cellular damage, which, in part, was mediated through the activation of the Sirt3/FoxO3a signaling pathway.
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Fu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China. Electronic address: hbwu029@nwsuaf.edu.cn.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling 712100, Shaanxi, China. Electronic address: yzhang1956@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002104:Cadmium / Q000633:toxicity; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015151:Immunoblotting; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002104:Cadmium; D048049:Extracellular Signal-Regulated MAP Kinases; D000071316:Forkhead Box Protein O3; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D056566:Sirtuin 3; D013267:Stilbenes; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse; C485290:Ppargc1a protein, mouse; C525046:Sirt3 protein, mouse
keywords: Cadmium; Mitochondria; Nephrotoxicity; Resveratrol; Sirt3