C3a and C5a promote renal ischemia-reperfusion injury.
Renal ischemia reperfusion injury triggers complement activation, but whether and how the small proinflammatory fragments C3a and C5a contribute to the pathogenesis of this injury remains to be elucidated. Using C3aR-, C5aR-, or C3aR/C5aR-deficient mice and models of renal ischemia-reperfusion injury, we found that deficiency of either or both of these receptors protected mice from injury, but the C3aR/C5aR- and C5aR-deficient mice were most protected. Protection from injury was associated with less cellular infiltration and lower mRNA levels of kidney injury molecule-1, proinflammatory mediators, and adhesion molecules in postischemic kidneys. Furthermore, chimera studies showed that the absence of C3aR and C5aR on renal tubular epithelial cells or circulating leukocytes attenuated renal ischemia-reperfusion injury. In vitro, C3a and C5a stimulation induced inflammatory mediators from both renal tubular epithelial cells and macrophages after hypoxia/reoxygenation. In conclusion, although both C3a and C5a contribute to renal ischemia-reperfusion injury, the pathogenic role of C5a in this injury predominates. These data also suggest that expression of C3aR and C5aR on both renal and circulating leukocytes contributes to the pathogenesis of renal ischemia-reperfusion injury.
MRC Centre for Transplantation, King's College London, London SE1 9RT, United Kingdom.
Qi
Q
Peng
Ke
K
Li
Lesley A
LA
Smyth
Guolan
G
Xing
Naiyin
N
Wang
Lucy
L
Meader
Bao
B
Lu
Steven H
SH
Sacks
Wuding
W
Zhou
D000818:Animals; D015926:Complement C3a / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015936:Complement C5a / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012039:Regional Blood Flow / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D015926:Complement C3a; D015936:Complement C5a