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Lookup NU author(s): Dr Kate Smith-Jackson, Dr Yi Yang, Harriet Denton, Katie Cooke, Professor David KavanaghORCiD, Professor Kevin MarchbankORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Smith-Jackson K, Yang Y, Denton H, Pappworth IY, Cooke K, Barlow PN, Atkinson JP, Liszewski MK, Pickering MC, Kavanagh D, Cook T, Marchbank KJ
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2019
Volume: 129
Issue: 3
Pages: 1061-1075
Print publication date: 01/03/2019
Online publication date: 04/02/2019
Acceptance date: 18/12/2018
Date deposited: 19/12/2018
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/JCI99296
DOI: 10.1172/JCI99296
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