ArticleThe Journal of clinical investigation2019
Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 32 citations in OpenAlex.
- Complement and kidney diseases: unlocking the opportunity of targeted treatments for glomerular diseases, including IgA nephropathy.Pediatric nephrology (Berlin, Germany) · 2026Review
- Serum complement C3 as a candidate biomarker for monitoring progression from chronic kidney disease to kidney failure.International urology and nephrology · 2026Article
- Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Complement-Mediated Kidney Diseases: Role of Alternative Pathway in Glomerular Inflammation.Kidney international reports · 2026Review
- Properdin deficiency or anti-properdin treatment ameliorates disease in the C3 gain-of-function mouse model of atypical haemolytic uraemic syndrome.Frontiers in immunology · 2026Article
- Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research.The Journal of clinical investigation · 2025Review
- Improved therapeutic efficacy of a bifunctional anti-C5 mAb-FH SCR1-5 fusion protein over anti-C5 mAb in an accelerated mouse model of C3 glomerulopathy.ImmunoHorizons · 2025Article
- Complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.BMC cardiovascular disorders · 2024Article
- Complement therapeutics are coming of age in rheumatology.Nature reviews. Rheumatology · 2023Review
- Plasminogen activator-coated nanobubbles targeting cellbound β2-glycoprotein I as a novel thrombus-specific thrombolytic strategy.Haematologica · 2023Article
- Low-molecular weight inhibitors of the alternative complement pathway.Immunological reviews · 2023Review
- Genetic variability shapes the alternative pathway complement activity and predisposition to complement-related diseases.Immunological reviews · 2023Review
- Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)-driven Complement-mediated Diseases.Immunological reviews · 2023Review
- Diagnosis and treatment of thrombotic microangiopathy.International journal of laboratory hematology · 2022Review
- The Rational Use of Complement Inhibitors in Kidney Diseases.Kidney international reports · 2022Review
- Patient-specific iPSC-derived endothelial cells reveal aberrant p38 MAPK signaling in atypical hemolytic uremic syndrome.Stem cell reports · 2021Article
- The Syndromes of Thrombotic Microangiopathy: A Critical Appraisal on Complement Dysregulation.Journal of clinical medicine · 2021Review
- Skeletal endocrinology: where evolutionary advantage meets disease.Bone research · 2021Review
- Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice.Scientific reports · 2021Article
- Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics.Advances in immunology · 2021Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.
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