title: Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia-reperfusion injury in mice.
abstract: OBJECTIVE
  Renal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia-reperfusion injury.
  
  
  METHODS
  Prospective, controlled, and randomized animal study.
  
  
  METHODS
  : A research institute laboratory.
  
  
  METHODS
  Male C57BL/6J mice (20-25 g).
  
  
  METHODS
  : Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG-E8 (0.4 μg/20 g) was given intraperitoneally at the beginning of reperfusion.
  
  
  RESULTS
  MFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice.
  
  
  CONCLUSIONS
  MFG-E8 can be developed as novel treatment for renal ischemia-reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.
authors.affiliation: Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, and The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsuda
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Komura
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Md Monowar
authors.initials: MM
authors.lastname: Aziz
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000517:prevention & control; D007511:Ischemia / Q000150:complications; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000503:physiopathology
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011994:Recombinant Proteins; D009195:Peroxidase