Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
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.
Date Issued
2019-02-04
Date Acceptance
2018-12-18
Citation
Journal of Clinical Investigation, 2019, 129 (3), pp.1061-1075
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
1061
End Page
1075
Journal / Book Title
Journal of Clinical Investigation
Volume
129
Issue
3
Copyright Statement
© 2019 Smith-Jackson et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30714990
PII: 99296
Subjects
Chronic kidney disease
Complement
Immunology
Innate immunity
Nephrology
Publication Status
Published online
Coverage Spatial
United States
Date Publish Online
2019-02-04