CD59a deficiency exacerbates ischemia-reperfusion injury in mice.
The terminal complement components C5a and the membrane attack complex are involved in the pathogenesis of ischemia-reperfusion injury in many organs. CD59 is the major regulator of membrane attack complex formation. Mice deficient in the Cd59a gene (mCd59a-/-) were used to investigate the role of CD59 in renal ischemia-reperfusion injury. Unilateral ischemia-reperfusion injury was induced by clamping the left renal pedicle for 30 minutes under general anesthetic. Mice were studied at 72 hours and 2 weeks after ischemia-reperfusion injury. mCd59a-/- mice developed significantly greater tubular injury (P = 0.01), tubulointerstitial apoptosis (P = 0.02), and neutrophil influx (P = 0.04) than controls at 72 hours after ischemia-reperfusion. Two weeks after ischemia-reperfusion, mCd59a-/- mice exhibited more severe tubular damage predominantly in a corticomedullary distribution than controls (P = 0.02). Quantification of interstitial leukocytes revealed significantly greater numbers of infiltrating lymphocytes (but not macrophages) in mCd59a-/- mice than controls (P = 0.04) at 2 weeks. At both time points, significantly more C9 (as a marker of membrane attack complex) deposition occurred in a peritubular distribution in mCd59a-/- mice than controls. In conclusion, these results demonstrate that the lack of CD59a, by allowing unregulated membrane attack complex deposition, exacerbates both the tubular injury and the interstitial leukocyte infiltrate after ischemia-reperfusion injury in mice.
Rheumatology Section, Eric Bywaters Centre, London, United Kingdom.
Daniel
D
Turnberg
Marina
M
Botto
Margarita
M
Lewis
Wuding
W
Zhou
Steven H
SH
Sacks
B Paul
BP
Morgan
Mark J
MJ
Walport
H Terence
HT
Cook
D000818:Animals; D017209:Apoptosis; D018957:CD59 Antigens / Q000502:physiology*; D003186:Complement C9 / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004195:Disease Models, Animal; D006720:Homozygote; D007684:Kidney Tubules / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
D018957:CD59 Antigens; D003186:Complement C9; D015938:Complement Membrane Attack Complex