Abstract |
Membranoproliferative glomerulonephritis (MPGN) type II ( dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh(-/-)). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh(-/-) mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed in Cfh(-/-) mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent in Cfh(-/-) mice deficient in C5 but not in Cfh(-/-) mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed in Cfh(-/-) mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II.
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Authors | M C Pickering, J Warren, K L Rose, F Carlucci, Y Wang, M J Walport, H T Cook, M Botto |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 25
Pg. 9649-54
(Jun 20 2006)
ISSN: 0027-8424 [Print] United States |
PMID | 16769899
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies
- Complement C5
- Complement C6
- Complement Factor H
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Topics |
- Animals
- Antibodies
(immunology, therapeutic use)
- Complement Activation
- Complement C5
(deficiency, genetics, immunology)
- Complement C6
(deficiency, genetics, metabolism)
- Complement Factor H
(deficiency, genetics, metabolism)
- Disease Models, Animal
- Glomerulonephritis
(genetics, metabolism, pathology, therapy)
- Mice
- Mice, Knockout
- Neutrophils
(cytology)
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