Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia-reperfusion injury in mice

Crit Care Med. 2011 Sep;39(9):2039-47. doi: 10.1097/CCM.0b013e3182227a3d.

Abstract

Objectives: 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.

Design: Prospective, controlled, and randomized animal study.

Setting: : A research institute laboratory.

Subjects: Male C57BL/6J mice (20-25 g).

Interventions: : 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.

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Surface / therapeutic use*
  • Apoptosis / drug effects
  • Blotting, Western
  • Disease Models, Animal
  • In Situ Nick-End Labeling
  • Inflammation / prevention & control
  • Ischemia / complications
  • Kidney / blood supply*
  • Kidney / drug effects
  • Kidney / physiopathology
  • Liver / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Milk Proteins / therapeutic use*
  • Peroxidase / metabolism
  • Recombinant Proteins / therapeutic use
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / physiopathology

Substances

  • Antigens, Surface
  • Mfge8 protein, mouse
  • Milk Proteins
  • Recombinant Proteins
  • Peroxidase