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 Moppett; Simon C Satchell; Gavin I Welsh; Patrick D Walker; Christoph Licht; Moin A Saleem; Richard J M Coward

doi:10.1016/j.medj.2023.09.002

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

Division of Cardiovascular Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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).

Original language	English
Journal	Med
DOIs	https://doi.org/10.1016/j.medj.2023.09.002
Publication status	E-pub ahead of print - 16 Oct 2023

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Bowen, E. E., Hurcombe, J. A., Barrington, F., Keir, L. S., Farmer, L. K., Wherlock, M. D., Ortiz-Sandoval, C. G., Bruno, V., Bohorquez-Hernandez, A., Diatlov, D., Rostam-Shirazi, N., Wells, S., Stewart, M., Teboul, L., Lay, A. C., Butler, M. J., Pope, R. J. P., Larkai, E. M. S., Morgan, B. P., ... Coward, R. J. M. (2023). Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation. Med. Advance online publication. https://doi.org/10.1016/j.medj.2023.09.002

@article{67d00b8d9361406fab39712012d538d6,

title = "Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation",

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).",

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

year = "2023",

month = oct,

day = "16",

doi = "10.1016/j.medj.2023.09.002",

language = "English",

journal = "Med",

issn = "2666-6340",

publisher = "Cell Press",

}

Bowen, EE, Hurcombe, JA, Barrington, F, Keir, LS, Farmer, LK, Wherlock, MD, Ortiz-Sandoval, CG, Bruno, V, Bohorquez-Hernandez, A, Diatlov, D, Rostam-Shirazi, N, Wells, S, Stewart, M, Teboul, L, Lay, AC, Butler, MJ, Pope, RJP, Larkai, EMS, Morgan, BP, Moppett, J, Satchell, SC, Welsh, GI, Walker, PD, Licht, C, Saleem, MA & Coward, RJM 2023, 'Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation', Med. https://doi.org/10.1016/j.medj.2023.09.002

TY - JOUR

T1 - Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation

AU - Bowen, Emily E

AU - Hurcombe, Jennifer A

AU - Barrington, Fern

AU - Keir, Lindsay S

AU - Farmer, Louise K

AU - Wherlock, Matthew D

AU - Ortiz-Sandoval, Carolina G

AU - Bruno, Valentina

AU - Bohorquez-Hernandez, Arlette

AU - Diatlov, Daniel

AU - Rostam-Shirazi, Niyousha

AU - Wells, Sara

AU - Stewart, Michelle

AU - Teboul, Lydia

AU - Lay, Abigail C

AU - Butler, Matthew J

AU - Pope, Robert J P

AU - Larkai, Eva M S

AU - Morgan, B Paul

AU - Moppett, John

AU - Satchell, Simon C

AU - Welsh, Gavin I

AU - Walker, Patrick D

AU - Licht, Christoph

AU - Saleem, Moin A

AU - Coward, Richard J M

PY - 2023/10/16

Y1 - 2023/10/16

N2 - 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).

AB - 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).

U2 - 10.1016/j.medj.2023.09.002

DO - 10.1016/j.medj.2023.09.002

M3 - Article

C2 - 37863058

SN - 2666-6340

JO - Med

JF - Med

ER -

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

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