ADAMTS7-Mediated Complement Factor H Degradation Potentiates Complement Activation to Contributing to Renal Injuries

Abstract

Significance Statement Complement factor H (CFH) dysfunction by an incomplete underlying mechanism causes various complement-mediated renal injuries. We identified metalloprotease ADAMTS7 as a novel binding protein of CFH that further degrades CFH and potentiates complement activation. ADAMTS7 deficiency alleviated CFH degradation and renal pathologies in lupus nephritis and renal ischemia-reperfusion injury in mice, but without affecting complement-dependent bactericidal activity. The investigation revealed a novel mechanism to explain CFH dysfunction in complement-mediated renal injuries. ADAMTS7 would be a promising target for anticomplement therapies that would potentially avoid increased risk of infection, which is the drawback of current strategies. Background The dysfunction of complement factor H (CFH), the main soluble complement negative regulator, potentiates various complement-induced renal injuries. However, insights into the underlying mechanism of CFH dysfunction remain limited. In this study, we investigated whether extracellular protease-mediated degradation accounts for CFH dysfunction in complement-mediated renal injuries. Methods An unbiased interactome of lupus mice kidneys identified CFH-binding protease. In vitro cleavage assay clarified CFH degradation. Pristane-induced SLE or renal ischemia-reperfusion (I/R) injury models were used in wild-type and ADAMTS7 −/− mice. Results We identified the metalloprotease ADAMTS7 as a CFH-binding protein in lupus kidneys. Moreover, the upregulation of ADAMTS7 correlated with CFH reduction in both lupus mice and patients. Mechanistically, ADAMTS7 is directly bound to CFH complement control protein (CCP) 1–4 domain and degraded CCP 1–7 domain through multiple cleavages. In mice with lupus nephritis or renal I/R injury, ADAMTS7 deficiency alleviated complement activation and related renal pathologies, but without affecting complement-mediated bactericidal activity. Adeno-associated virus–mediated CFH silencing compromised these protective effects of ADAMTS7 knockout against complement-mediated renal injuries in vivo. Conclusion ADAMTS7-mediated CFH degradation potentiates complement activation and related renal injuries. ADAMTS7 would be a promising anticomplement therapeutic target that does not increase bacterial infection risk.