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

Child Humans Mice Animals Podocytes / metabolism Shiga Toxin / genetics Vascular Endothelial Growth Factor A / metabolism Escherichia coli Infections / complications Hemolytic-Uremic Syndrome / drug therapy Shiga-Toxigenic Escherichia coli / metabolism Complement Activation Kidney Diseases / pathology

Pre-clinical research pre-clinical research

Journal

Med (New York, N.Y.)

ISSN: 2666-6340

Titre abrégé: Med

Pays: United States

ID NLM: 101769215

Informations de publication

Date de publication:
10 11 2023

Historique:

received: 09 03 2023

revised: 18 07 2023

accepted: 18 09 2023

medline: 13 11 2023

pubmed: 21 10 2023

entrez: 20 10 2023

Statut: ppublish

Résumé

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. 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. 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. 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. 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).

Sections du résumé

BACKGROUND

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).

Identifiants

DOI: 10.1016/j.medj.2023.09.002 PMID: 37863058

pubmed: 37863058

pii: S2666-6340(23)00289-1

doi: 10.1016/j.medj.2023.09.002

pii:

doi:

Substances chimiques

Shiga Toxin 75757-64-1

Vascular Endothelial Growth Factor A 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng