ADAMTS7-Mediated Complement Factor H Degradation Potentiates Complement Activation to Contributing to Renal Injuries
Zihan Ma1, Chenfeng Mao1,2, Yiting Jia1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
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.
Insights
Extracellular protease ADAMTS7 degrades complement factor H (CFH), worsening kidney injury. Targeting ADAMTS7 may treat complement-mediated renal diseases without increasing infection risk.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Complement factor H (CFH) dysfunction is linked to renal injuries.
- Mechanisms of CFH dysfunction in kidney disease are not fully understood.
Purpose of the Study:
- Investigate extracellular protease-mediated degradation as a cause of CFH dysfunction.
- Explore the role of ADAMTS7 in complement-mediated renal injuries.
Main Methods:
- Identified CFH-binding proteases in lupus mouse kidneys using interactome analysis.
- Performed in vitro cleavage assays to confirm CFH degradation by ADAMTS7.
- Utilized lupus nephritis and renal ischemia-reperfusion (I/R) injury models in wild-type and ADAMTS7 knockout mice.
Main Results:
- ADAMTS7 was identified as a CFH-binding protease that degrades CFH.
- ADAMTS7 upregulation correlated with CFH reduction in lupus models and patients.
- ADAMTS7 deficiency protected against renal injury by reducing complement activation, without impairing bacterial defense.
- CFH silencing reversed the protective effects of ADAMTS7 deficiency.
Conclusions:
- ADAMTS7-mediated CFH degradation drives complement activation and renal injury.
- ADAMTS7 represents a potential therapeutic target for anticomplement therapy with a low risk of infection.
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