title: Caspase-Dependent and Caspase-Independent Pathways Are Involved in Cadmium-Induced Apoptosis in Primary Rat Proximal Tubular Cell Culture.
abstract: We designed this study to investigate whether cadmium induces caspase-independent apoptosis and to investigate the relationship between the caspase-dependent and caspase-independent apoptotic pathways. Cadmium (1.25-2.5 μM) induced oxidative stress in rat proximal tubular (rPT) cells, as seen in the reactive oxygen species levels; N-acetylcysteine prevented this. Cyclosporin A (CsA) prevented mitochondrial permeability transition pore opening and apoptosis; there was mitochondrial ultrastructural disruption, mitochondrial cytochrome c (cyt c) translocation to the cytoplasm, and subsequent caspase-9 and caspase-3 activation. Z-VAD-FMK prevented caspase-3 activation and apoptosis and decreased BNIP-3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) expression levels and apoptosis-inducing factor/endonuclease G (AIF/Endo G) translocation. Simultaneously, cadmium induced prominent BNIP-3 expression in the mitochondria and cytoplasmic AIF/Endo G translocation to the nucleus. BNIP-3 silencing significantly prevented AIF and Endo G translocation and decreased the apoptosis rate, cyt c release, and caspase-9 and caspase-3 activation. These results suggest that BNIP-3 is involved in the caspase-independent apoptotic pathway and is located upstream of AIF/Endo G; both the caspase-dependent and caspase-independent pathways are involved in cadmium-induced rPT cell apoptosis and act synergistically.
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Tongwang
authors.initials: T
authors.lastname: Luo
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Mengfei
authors.initials: M
authors.lastname: Long
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Bian
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Gu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Ruilong
authors.initials: R
authors.lastname: Song
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Jiaqiao
authors.initials: J
authors.lastname: Zhu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, and Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, PR China.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000494:pharmacology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D020868:Gene Silencing; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C505650:BNIP3 protein, rat; D061945:Caspase Inhibitors; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D002104:Cadmium; D045304:Cytochromes c; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases