title: Ectopic overexpression of haem oxygenase-1 protects kidneys from carboplatin-mediated apoptosis.
abstract: OBJECTIVE
  We previously reported that the activation of the nuclear factor of activated T-lymphocyte-3 (NFAT3) by carboplatin leads to renal apoptosis as a result of oxidative stress, which is reversed by N-acetylcysteine. Herein, we extend our previous work to provide evidence of the molecular mechanisms of haem oxygenase (HO)-1 in protecting against injury.
  
  
  METHODS
  Protective mechanisms of HO-1 in carboplatin-mediated renal apoptosis were examined in C57BL/6 mice and rat renal tubular cells (RTC) with HO-1 induction or inactivation/knockdown.
  
  
  RESULTS
  The HO-1, induced by cobalt protoporphyrin, protected against carboplatin-induced renal injury in vivo. This protection was decreased by an inhibitor of HO-1 action, tin protoporphyrin. In cultures of RTC, carboplatin-induced apoptosis was similarly affected by HO-1 overexpression or knockdown. Carboplatin-mediated NFAT3 activation and apoptosis involve activation of the signalling kinases, extracellular signal regulated kinase, Jun N-terminal kinase and protein kinase C, and such activation was reversed in cells overexpressing HO-1. Both products of the HO-1 reaction, CO and bilirubin, inhibited (by 30-40%) NFAT3 activation and production of the pro-apoptotic proteins Bcl-XS/Bax. Additionally, the activation of NFκB was markedly decreased by HO-1 induction.
  
  
  CONCLUSIONS
  HO-1 and its reaction products show anti-apoptotic effects in carboplatin-mediated renal injury. A novel functional NFAT3 binding site identified in the rat HO-1 promoter region was involved in producing a 1.5-fold to 2.5-fold increase in HO-1 induction by carboplatin. Nevertheless, only HO-1 overexpression and activation prior to the carboplatin challenge provided protection against carboplatin-induced injury.
authors.affiliation: Department of Nephrology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Yuh-Mou
authors.initials: YM
authors.lastname: Sue
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Chou
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chang
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Lee
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Juan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D016190:Carboplatin / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D050778:NFATC Transcription Factors; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D016190:Carboplatin; D051547:Heme Oxygenase-1