title: CCAAT-Enhancer-Binding Protein Homologous Protein Deficiency Attenuates Oxidative Stress and Renal Ischemia-Reperfusion Injury.
abstract: OBJECTIVE
  Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. The mechanisms of I/R injury include endoplasmic reticulum (ER) stress, inflammatory responses, hypoxia, and generation of reactive oxygen species (ROS). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still undefined. Here, we investigated whether CHOP could regulate I/R-induced renal injury using CHOP-knockout mice and cultured renal tubular cells as models.
  
  
  RESULTS
  In CHOP-knockout mice, loss of renal function induced by I/R was prevented. Renal proximal tubule damage was induced by I/R in wild-type mice; however, the degree of alteration was significantly less in CHOP-knockout mice. CHOP deficiency also decreased the I/R-induced activation of caspase-3 and -8, apoptosis, and lipid peroxidation, whereas the activity of endogenous antioxidants increased. In an in vitro I/R model, small interfering RNA targeting CHOP significantly reversed increases in H2O2 formation, inflammatory signals, and apoptotic signals, while enhancing the activity of endogenous antioxidants in renal tubular cells.
  
  
  METHODS
  To the best of our knowledge, this is the first study which demonstrates that CHOP deficiency attenuates oxidative stress and I/R-induced acute renal injury both in vitro and in vivo.
  
  
  CONCLUSIONS
  These findings suggest that CHOP regulates not only apoptosis-related signaling but also ROS formation and inflammation in renal tubular cells during I/R. CHOP may play an important role in the pathophysiology of I/R-induced renal injury.
authors.affiliation: 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .
authors.forename: Bo Lin
authors.initials: BL
authors.lastname: Chen
authors.affiliation: 2 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: 3 Department of Laboratory Medicine, College of Medicine, National Taiwan University , Taipei, Taiwan .
authors.forename: Keh Sung
authors.initials: KS
authors.lastname: Tsai
authors.affiliation: 4 Department of Emergency Medicine, National Defense Medical Center, Tri-Service General Hospital , Taipei, Taiwan .
authors.forename: Kuo Cheng
authors.initials: KC
authors.lastname: Lan
authors.affiliation: 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .
authors.forename: Siao Syun
authors.initials: SS
authors.lastname: Guan
authors.affiliation: 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .
authors.forename: Cheng Tien
authors.initials: CT
authors.lastname: Wu
authors.affiliation: 5 Department of Dentistry, Taipei Chang Gang Memorial Hospital, Chang Gang University , Taipei, Taiwan .
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: 6 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine , Taipei, Taiwan .
authors.forename: Kuan Yu
authors.initials: KY
authors.lastname: Hung
authors.affiliation: 6 Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine , Taipei, Taiwan .
authors.forename: Jenq Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .|7 Department of Integrated Diagnostics and Therapeutics, College of Medicine and Hospital, National Taiwan University , Taipei, Taiwan .
authors.forename: Chih Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: 1 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .|8 Department of Medical Research, China Medical University Hospital, China Medical University , Taichung, Taiwan .|9 Department of Pediatrics, National Taiwan University Hospital , Taipei, Taiwan .
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D015227:Lipid Peroxidation; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; C497250:Ddit3 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D005978:Glutathione; C027576:4-hydroxy-2-nonenal