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Hyper-functional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice

Lookup NU author(s): Dr Kate Smith-Jackson, Dr Yi Yang, Harriet Denton, Katie Cooke, Professor David Kavanagh, Dr Kevin Marchbank

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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

Pages: ePub ahead of Print

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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