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Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.

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.
AuthorsM C Pickering, J Warren, K L Rose, F Carlucci, Y Wang, M J Walport, H T Cook, M Botto
JournalProceedings 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
PMID16769899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • Complement C5
  • Complement C6
  • Complement Factor H
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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