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Lookup NU author(s): Dr Kate Smith-Jackson, Dr Patrick WalshORCiD, Dr Gemma Thompson, Dr Beth Gibson, Chloe Connelly, Dr Isabel Pappworth, Professor David KavanaghORCiD, Professor Kevin MarchbankORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The C3D1115N mouse, engineered around a gain of function point mutation in C3 associated with complement mediated atypical haemolytic uraemic syndrome in man, recapitulates the clinical disease. Backcrossing our model onto C7 deficient and C5aR1 deficient mice enabled us to further determine the roles of the C5a-C5aR1 axis and C5b-9 (the membrane attack complex) on kidney disease. C7 deficiency completely abolished both clinical and histological evidence of disease. We found that removing C5aR1 (CD88) attenuated the risk of developing clinical disease, but mice could still develop a thrombotic microangiopathy. Therapeutic inhibition consolidated our genetic findings, showing that both anti-C7 therapy and an oral C5aR1 antagonist when used before evidence of significant renal injury, prevented mice from succumbing to disease. However, there was ongoing histological disease within mice treated with the C5aR1 antagonist. Our data suggest that both C5aR1 and C7 play a role in the development of the conditions required for renal thrombotic microangiopathy. While disrupting the C5a-C5aR1 axis is beneficial, our genetic and therapeutic studies showed that a renal thrombotic microangiopathy can still develop and ultimately our data confirms that the membrane attack complex is required to develop renal thrombotic microangiopathy. Thus, as well as the requirement for alternative pathway dysregulation, local generation of membrane attack complex within the kidney is also critical to drive disease pathology in complement mediated aHUS.
Author(s): Smith-Jackson K, Walsh P, Zelek WM, Hoyler T, Martinic MM, Thompson G, Gibson BG, Connelly C, Pappworth IY, Murphy MJ, Kavanagh D, Marchbank KJ
Publication type: Article
Publication status: Published
Journal: Kidney International
Year: 2025
Pages: Epub ahead of print
Online publication date: 21/01/2025
Acceptance date: 16/12/2024
Date deposited: 17/12/2024
ISSN (print): 0085-2538
ISSN (electronic): 1523-1755
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.kint.2024.12.016
DOI: 10.1016/j.kint.2024.12.016
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