Exogenous alpha-1-acid glycoprotein protects against renal ischemia-reperfusion injury by inhibition of inflammation and apoptosis.
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.
de Vries
Bart
B
Department of Surgery, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Academic Hospital Maastricht and Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, the Netherlands.
Walter
Sarah J
SJ
Wolfs
Tim G A M
TG
Hochepied
Tino
T
Räbinä
Jarkko
J
Heeringa
Peter
P
Parkkinen
Jaakko
J
Libert
Claude
C
Buurman
Wim A
WA
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*
D009961:Orosomucoid; D005643:Fucose