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.
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Authors | Elena Goicoechea de Jorge, Paolo Macor, Danielle Paixão-Cavalcante, Kirsten L Rose, Franco Tedesco, H Terence Cook, Marina Botto, Matthew C Pickering |
Journal | Journal of the American Society of Nephrology : JASN
(J Am Soc Nephrol)
Vol. 22
Issue 1
Pg. 137-45
(Jan 2011)
ISSN: 1533-3450 [Electronic] United States |
PMID | 21148255
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Complement C3
- Complement C5
- Complement C9
- Complement Factor H
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Topics |
- Animals
- Atypical Hemolytic Uremic Syndrome
- Complement C3
(metabolism)
- Complement C5
(deficiency, genetics, physiology)
- Complement C9
(metabolism)
- Complement Factor H
(deficiency, genetics, physiology)
- Disease Models, Animal
- Glomerular Mesangium
(metabolism)
- Hemolytic-Uremic Syndrome
(physiopathology)
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Knockout
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