Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/37863058http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/37863058http://www.w3.org/2000/01/rdf-schema#comment"

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)."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.org/dc/terms/identifier"doi:10.1016/j.medj.2023.09.002"xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Stewart M."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Butler M.J."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Morgan B.P."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Saleem M.A."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Welsh G.I."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Wells S."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Bruno V."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Licht C."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Satchell S.C."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Keir L.S."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Teboul L."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Walker P.D."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Moppett J."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Barrington F."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Coward R.J.M."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Hurcombe J.A."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Farmer L.K."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Ortiz-Sandoval C.G."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Bohorquez-Hernandez A."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Lay A.C."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Pope R.J.P."xsd:string
http://purl.uniprot.org/citations/37863058http://purl.uniprot.org/core/author"Bowen E.E."xsd:string
▶