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

Emily E Bowen, Jennifer A Hurcombe, Fern Barrington, Lindsay S Keir, Louise K Farmer, Matthew D Wherlock, Carolina G Ortiz-Sandoval, Valentina Bruno, Arlette Bohorquez-Hernandez, Daniel Diatlov, Niyousha Rostam-Shirazi, Sara Wells, Michelle Stewart, Lydia Teboul, Abigail C Lay, Matthew J Butler, Robert J P Pope, Eva M S Larkai, B Paul Morgan, John MoppettSimon C Satchell, Gavin I Welsh, Patrick D Walker, Christoph Licht, Moin A Saleem, Richard J M Coward

Research output: Contribution to journalArticlepeer-review


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.

FUNDING: This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

Original languageEnglish
Publication statusE-pub ahead of print - 16 Oct 2023


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