title: The development of atypical hemolytic uremic syndrome depends on complement C5.
abstract: Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.
authors.affiliation: Complement and Inflammation Section, Division of Immunology and Inflammation, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, United Kingdom.
authors.forename: Elena Goicoechea
authors.initials: EG
authors.lastname: de Jorge
authors.forename: Paolo
authors.initials: P
authors.lastname: Macor
authors.forename: Danielle
authors.initials: D
authors.lastname: Paixão-Cavalcante
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Rose
authors.forename: Franco
authors.initials: F
authors.lastname: Tedesco
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D065766:Atypical Hemolytic Uremic Syndrome; D003176:Complement C3 / Q000378:metabolism; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003186:Complement C9 / Q000378:metabolism; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout
chemical_list: D003176:Complement C3; D003182:Complement C5; D003186:Complement C9; D017242:Complement Factor H