title: C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy.
abstract: C3 glomerulopathy is a potentially life-threatening disease of the kidney caused by dysregulated alternative pathway complement activation. The specific complement mediator(s) responsible for kidney injury in C3 glomerulopathy are yet to be defined and no specific therapy is currently available. We previously developed a mouse model of lethal C3 glomerulopathy with factor H and properdin gene double mutations. Therefore, we used this model to examine the role of C5 and C5a receptor (C5aR) in the pathogenesis of the disease. Disease severity in these factor H/properdin double-mutant mice was found to be correlated with plasma C5 levels, and prophylactic anti-C5 mAb therapy was effective in preventing lethal C3 glomerulopathy. When given to these double-mutant mice that had already developed active disease with severe proteinuria, anti-C5 mAb treatment also prevented death in half of the mice. Deficiency of C5aR significantly reduced disease severity, suggesting that C5aR-mediated inflammation contributed to C3 glomerulopathy. Thus, C5 and C5aR have a critical role in C3 glomerulopathy. Hence, early intervention targeting these pathways may be an effective therapeutic strategy for patients with C3 glomerulopathy.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Allison Lesher
authors.initials: AL
authors.lastname: Williams
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Damodar
authors.initials: D
authors.lastname: Gullipalli
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Tung
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: songwe@upenn.edu.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism*; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011414:Properdin / Q000172:deficiency / Q000235:genetics; D011507:Proteinuria / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics; D051437:Renal Insufficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; C545610:C3 protein, mouse; D003176:Complement C3; D003182:Complement C5; D051056:Complement Inactivating Agents; D044087:Receptor, Anaphylatoxin C5a; D011414:Properdin; D017242:Complement Factor H
keywords: C3 glomerulopathy; C5; C5a receptor; complement factor H; properdin