title: Exogenous alpha-1-acid glycoprotein protects against renal ischemia-reperfusion injury by inhibition of inflammation and apoptosis.
abstract: BACKGROUND
  Although ischemia-reperfusion (I/R) injury represents a major problem in posttransplant organ failure, effective treatment is not available. The acute phase protein alpha-1-acid glycoprotein (AGP) has been shown to be protective against experimental I/R injury. The effects of AGP are thought to be mediated by fucose groups expressed on the AGP protein inhibiting neutrophil infiltration. However, the precise mechanism of protection remains to be established. We therefore studied the effects of exogenous human AGP (hAGP) in a mouse model of ischemic acute renal failure.
  
  
  METHODS
  Mice were subjected to renal I/R and treated with hAGP, fucose-depleted hAGP, or control treated. Also, transgenic mice over-expressing rat AGP or wild-type controls were subjected to renal I/R.
  
  
  RESULTS
  Treatment was with hAGP as well as fucose-depleted hAGP protected mice against I/R-induced acute renal failure. Surprisingly, AGP-over-expressing mice were not protected against I/R injury. Both natural and fucose-depleted hAGP inhibited the activation of the complement system, as determined by renal C3 deposition and influx of neutrophils measured by immunohistochemistry and myeloperoxidase-enzyme-linked immunoadsorbent assay. Tubular epithelial cell structure (actin cytoskeleton) and cell-cell interaction (tight-junction architecture) were completely preserved in AGP-treated mice. Also, epithelial caspase activation and apoptotic DNA cleavage were prevented by AGP treatment.
  
  
  CONCLUSIONS
  Both natural and fucose-depleted hAGP protect against renal I/R injury by preservation of tubular epithelial structure and inhibition of apoptosis and subsequent inflammation. Therefore, hAGP can be regarded as a potential new therapeutic intervention in the treatment of acute renal failure, as seen after transplantation of ischemically injured kidneys.
authors.affiliation: Department of Surgery, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Academic Hospital Maastricht and Maastricht University, Universiteitssingel 50, 6200 MD 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: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.forename: Jarkko
authors.initials: J
authors.lastname: Räbinä
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Jaakko
authors.initials: J
authors.lastname: Parkkinen
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005643:Fucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009961:Orosomucoid / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D009961:Orosomucoid; D005643:Fucose