Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation
Year: 2023
Type: article
Abstract: 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).
Source: Med
Authors: 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 Moppett, Simon C. Satchell, Gavin I. Welsh, Patrick D. Walker, Christoph Licht, Moin A. Saleem, Richard J.M. Coward
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $8,900
Awards: Targeting endothelial and erythrocyte glcocalicies for the novel diagnosis and treatment of renal disease, G1409327439, G2007715586, G2190735534, G233902614, G2463381737, G3825496574, Identifying New Molecular Pathways and Therapeutic Targets in Diabetic Kidney Disease, G5049997570, G5506955688, Is Diabetic Nephropathy the Result of a Podocyte Tauopathy?, G6954555546, G8173290873, G8196176567, Aldosterone-induced endothelial glycocalyx dysfunction, a potential therapeutic target in proteinuria?, Insulin signalling to the podocyte; pathological importance and therapeutic potential.
OpenAlex ID: W4387773293