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.
Journal of the American Society of Nephrology : JASN
|February 3, 2023
Summary
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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