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Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation

Bowen, Emily E., Hurcombe, Jennifer A., Barrington, Fern, Keir, Lindsay S., Farmer, Louise K., Wherlock, Matthew D., Ortiz-Sandoval, Carolina G., Bruno, Valentina, Bohorquez-Hernandez, Arlette, Diatlov, Daniel, Rostam-Shirazi, Niyousha, Wells, Sara, Stewart, Michelle, Teboul, Lydia, Lay, Abigail C., Butler, Matthew J., Pope, Robert J.P., Larkai, Eva M.S., Morgan, B. Paul, Moppett, John, Satchell, Simon C., Welsh, Gavin I., Walker, Patrick D., Licht, Christoph, Saleem, Moin A. and Coward, Richard J.M. 2023. Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation. Med 4 (11) 10.1016/j.medj.2023.09.002

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Background: Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear. Methods: Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied. Findings: Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype. Conclusions: This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Cell Press
ISSN: 2666-6340
Date of First Compliant Deposit: 23 November 2023
Date of Acceptance: 18 September 2023
Last Modified: 27 Nov 2023 12:02

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