title: Reduction of circulating redox-active iron by apotransferrin protects against renal ischemia-reperfusion injury.
abstract: BACKGROUND
  Warm ischemia-reperfusion (I/R) injury plays an important role in posttransplant organ failure. In particular, organs from marginal donors suffer I/R injury. Although iron has been implicated in the pathophysiology of renal I/R injury, the mechanism of iron-mediated injury remains to be established. The authors therefore investigated the role of circulating redox-active iron in an experimental model for renal I/R injury.
  
  
  METHODS
  Male Swiss mice were subjected to unilateral renal ischemia for 45 min, followed by contralateral nephrectomy and reperfusion. To investigate the role of circulating iron, mice were treated with apotransferrin, an endogenous iron-binding protein, or iron-saturated apotransferrin (holotransferrin).
  
  
  RESULTS
  Renal ischemia induced a significant increase in circulating redox-active iron levels during reperfusion. Apotransferrin, in contrast to holotransferrin, reduced the amount of circulating redox-active iron and abrogated renal superoxide formation. Apotransferrin treatment did not affect I/R-induced renal apoptosis, whereas holotransferrin aggravated apoptotic cell death. Apotransferrin, in contrast to holotransferrin, inhibited the influx of neutrophils. Both apo- and holotransferrin reduced I/R-induced complement deposition, indicating that the effects of transferrin are differentially mediated by its iron and protein moiety. Finally, apotransferrin, in contrast to holotransferrin, dose-dependently inhibited the loss of renal function induced by ischemia.
  
  
  CONCLUSIONS
  Redox-active iron is released into the circulation in the course of renal I/R. Reducing the amount of circulating redox-active iron by treatment with apotransferrin protects against renal I/R injury, inhibiting oxidative stress, inflammation, and loss of function. Apotransferrin could be used in the treatment of acute renal failure, as seen after transplantation of ischemically damaged organs.
authors.affiliation: Department of Surgery, Nutrition and Toxicology Research Institute Maastricht, Academic Hospital Maastricht, Maastricht, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: de Vries
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Walter
authors.forename: Leni
authors.initials: L
authors.lastname: von Bonsdorff
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.forename: L W Ernest
authors.initials: LW
authors.lastname: van Heurn
authors.forename: Jaakko
authors.initials: J
authors.lastname: Parkkinen
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D003167:Complement Activation; D007501:Iron / Q000097:blood*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009392:Nephrectomy; D009504:Neutrophils / Q000276:immunology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000097:blood; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism / Q000494:pharmacology*; D019737:Transplants / Q000009:adverse effects
chemical_list: D001059:Apoproteins; D017382:Reactive Oxygen Species; D014168:Transferrin; C028284:apotransferrin; C110714:holotransferrin; D007501:Iron