Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils.
The complement system has been shown to mediate renal ischemia-reperfusion (I/R) injury. However, the contribution of complement factor C5a to I/R injury, in particular in the kidney, remains to be established. In this study, we investigated the impact of blocking the C5aR pathway on the inflammatory response and on the renal function in a murine model of I/R injury. First, we analyzed C5aR expression in kidneys of healthy mice. Intriguingly, we found expression on mesangial, as well as on tubular epithelial, cells. After I/R injury, C5aR expression was up-regulated in tubular epithelial cells. In addition, mRNA levels of CXC chemokines and TNF-alpha increased significantly and kidneys were heavily infiltrated by neutrophils. Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-alpha and reduced neutrophil infiltration by >50%. Moreover, application of the C5aRA significantly reduced loss of renal function. This improvement of function was independent of the presence of neutrophils because neutrophil depletion by mAb NIMP-R14 did not affect the protective effect of C5aRA treatment. Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis. These data provide evidence that C5a is crucially involved in the pathogenesis of renal I/R injury by modulation of neutrophil-dependent as well as neutrophil-independent pathways, which include the regulation of CXC chemokines but not TNF-alpha or apoptotic pathways.
de Vries
Bart
B
Department of General Surgery, Nutrition and Toxicology Research Institute Maastricht, The Netherlands.
Köhl
Jörg
J
Leclercq
Wouter K G
WK
Wolfs
Tim G A M
TG
van Bijnen
Annemarie A J H M
AA
Heeringa
Peter
P
Buurman
Wim A
WA
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis; D002630:Chemotactic Factors / Q000096:biosynthesis; D015936:Complement C5a / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007668:Kidney / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D015846:Monokines / Q000096:biosynthesis; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015846:Monokines; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a