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C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy
Allison Lesher Williams1, Damodar Gullipalli1, Yoshiyasu Ueda1
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Insights
Complement C5 and its receptor C5aR are critical drivers of C3 glomerulopathy, a severe kidney disease. Targeting these pathways with therapies like anti-C5 mAb shows promise for treating this condition.
Area of Science:
- Nephrology
- Immunology
- Complement System Biology
Background:
- C3 glomerulopathy (C3G) is a severe kidney disease driven by complement dysregulation.
- The specific complement components causing kidney injury and effective treatments for C3G remain undefined.
Purpose of the Study:
- To investigate the role of the complement component C5 and its receptor C5aR in the pathogenesis of C3G.
- To evaluate the therapeutic potential of targeting C5 and C5aR in a mouse model of lethal C3G.
Main Methods:
- Utilized a previously established mouse model with double mutations in factor H and properdin genes, mimicking lethal C3G.
- Administered anti-C5 monoclonal antibody (mAb) prophylactically and therapeutically.
- Assessed disease severity and survival in mice with C5aR deficiency.
Main Results:
- Disease severity in the C3G mouse model correlated with plasma C5 levels.
- Prophylactic anti-C5 mAb therapy prevented lethal C3G.
- Therapeutic anti-C5 mAb treatment improved survival in mice with established severe disease.
- C5aR deficiency significantly reduced C3G severity, indicating a role for C5aR-mediated inflammation.
Conclusions:
- C5 and C5aR play critical roles in the pathogenesis of C3 glomerulopathy.
- Targeting the C5/C5aR pathway represents a potential therapeutic strategy for C3G.
- Early intervention targeting C5 and C5aR may offer a novel treatment approach for C3G patients.
Abstract:
C3 glomerulopathy is a potentially life-threatening disease of the kidney caused by dysregulated alternative pathway complement activation. The specific complement mediator(s) responsible for kidney injury in C3 glomerulopathy are yet to be defined and no specific therapy is currently available. We previously developed a mouse model of lethal C3 glomerulopathy with factor H and properdin gene double mutations. Therefore, we used this model to examine the role of C5 and C5a receptor (C5aR) in the pathogenesis of the disease. Disease severity in these factor H/properdin double-mutant mice was found to be correlated with plasma C5 levels, and prophylactic anti-C5 mAb therapy was effective in preventing lethal C3 glomerulopathy. When given to these double-mutant mice that had already developed active disease with severe proteinuria, anti-C5 mAb treatment also prevented death in half of the mice. Deficiency of C5aR significantly reduced disease severity, suggesting that C5aR-mediated inflammation contributed to C3 glomerulopathy. Thus, C5 and C5aR have a critical role in C3 glomerulopathy. Hence, early intervention targeting these pathways may be an effective therapeutic strategy for patients with C3 glomerulopathy.
