Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.
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.
Pickering
M C
MC
Rheumatology Section and Department of Histopathology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. matthew.pickering@imperial.ac.uk
Warren
J
J
Rose
K L
KL
Carlucci
F
F
Wang
Y
Y
Walport
M J
MJ
Cook
H T
HT
Botto
M
M
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D003167:Complement Activation; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017242:Complement Factor H / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology
D000906:Antibodies; D003182:Complement C5; D003183:Complement C6; D017242:Complement Factor H