title: Blocking properdin, the alternative pathway, and anaphylatoxin receptors ameliorates renal ischemia-reperfusion injury in decay-accelerating factor and CD59 double-knockout mice.
abstract: Complement is implicated in the pathogenesis of ischemia-reperfusion injury (IRI). The activation pathway(s) and effector(s) of complement in IRI may be organ specific and remain to be fully characterized. We previously developed a renal IRI model in decay-accelerating factor (DAF) and CD59 double-knockout (DAF(-/-)CD59(-/-)) mice. In this study, we used this model to dissect the pathway(s) by which complement is activated in renal IRI and to evaluate whether C3aR- or C5aR-mediated inflammation or the membrane attack complex was pathogenic. We crossed DAF(-/-)CD59(-/-) mice with mice deficient in various complement components or receptors including C3, C4, factor B (fB), factor properdin (fP), mannose-binding lectin, C3aR, C5aR, or Ig and assessed renal IRI in the resulting mutant strains. We found that deletion of C3, fB, fP, C3aR, or C5aR significantly ameliorated renal IRI in DAF(-/-)CD59(-/-) mice, whereas deficiency of C4, Ig, or mannose-binding lectin had no effect. Treatment of DAF(-/-)CD59(-/-) mice with an anti-C5 mAb reduced renal IRI to a greater degree than did C5aR deficiency. We also generated and tested a function-blocking anti-mouse fP mAb and showed it to ameliorate renal IRI when given to DAF(-/-)CD59(-/-) mice 24 h before, but not 4 or 8 h after, ischemia/reperfusion. These results suggest that complement is activated via the alternative pathway during the early phase of reperfusion, and both anaphylatoxin-mediated inflammation and the membrane attack complex contribute to tissue injury. Further, they demonstrate a critical role for properdin and support its therapeutic targeting in renal IRI.
authors: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Takashi
authors: T
authors: Miwa
authors: Sayaka
authors: S
authors: Sato
authors: Damodar
authors: D
authors: Gullipalli
authors: Masaomi
authors: M
authors: Nangaku
authors: Wen-Chao
authors: WC
authors: Song
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018958:CD55 Antigens / Q000235:genetics*; D018957:CD59 Antigens / Q000235:genetics*; D003176:Complement C3 / Q000172:deficiency / Q000276:immunology; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011414:Properdin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000235:genetics* / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D044087:Receptor, Anaphylatoxin C5a; D011414:Properdin; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B