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Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice
M C Pickering1, J Warren, K L Rose
1Rheumatology 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
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.
Insights
Complement C5 activation drives kidney damage in Membranoproliferative glomerulonephritis (MPGN) type II. Inhibiting C5 may offer a new therapeutic strategy for this inflammatory renal disease.
Area of Science:
- Nephrology
- Immunology
- Complement System
Background:
- Membranoproliferative glomerulonephritis (MPGN) type II, also known as dense deposit disease, is a severe inflammatory kidney disease.
- Current therapeutic options for MPGN type II are limited, highlighting the need for novel treatment strategies.
Purpose of the Study:
- To investigate the role of complement C5 activation in the pathogenesis of MPGN type II.
- To evaluate the therapeutic potential of C5 inhibition in a mouse model of MPGN.
Main Methods:
- Utilized complement factor H-deficient (Cfh(-/-)) mice, which spontaneously develop MPGN.
- Administered anti-murine C5 antibody to Cfh(-/-) mice to assess the effects of C5 inhibition on renal injury.
- Induced nephritis in Cfh(-/-) mice using an anti-glomerular basement membrane antibody to model disease flares.
Main Results:
- Cfh(-/-) mice deficient in C5 exhibited reduced mortality, glomerular inflammation, and improved kidney function.
- C5 deficiency abrogated the exaggerated renal injury observed after antibody-induced nephritis in Cfh(-/-) mice.
- Pretreatment with an anti-murine C5 antibody completely reversed established renal injury in Cfh(-/-) mice.
Conclusions:
- Complement C5 activation plays a critical role in both spontaneous and experimentally induced renal lesions in factor H-deficient mice.
- C5 inhibition demonstrates significant therapeutic potential for treating MPGN type II and related inflammatory kidney diseases.
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