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

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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 inCfh−/−mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed inCfh−/−mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent inCfh−/−mice deficient in C5 but not inCfh−/−mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed inCfh−/−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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