Abstract
Background
Shiga toxin-producing Escherichia coli is responsible for post-diarrheal (D+) hemolytic uremic syndrome (HUS), which is a cause of acute renal failure in children. The glycolipid globotriaosylceramide (Gb3) is the main receptor for Shiga toxin (Stx) in kidney target cells. Eliglustat (EG) is a specific and potent inhibitor of glucosylceramide synthase, first step of glycosphingolipid biosynthesis, actually used for the treatment of Gaucher’s disease. The aim of the present work was to evaluate the efficiency of EG in preventing the damage caused by Stx2 in human renal epithelial cells.
Methods
Human renal tubular epithelial cell (HRTEC) primary cultures were pre-treated with different dilutions of EG followed by co-incubation with EG and Stx2 at different times, and cell viability, proliferation, apoptosis, tubulogenesis, and Gb3 expression were assessed.
Results
In HRTEC, pre-treatments with 50 nmol/L EG for 24 h, or 500 nmol/L EG for 6 h, reduced Gb3 expression and totally prevented the effects of Stx2 on cell viability, proliferation, and apoptosis. EG treatment also allowed the development of tubulogenesis in 3D-HRTEC exposed to Stx2.
Conclusions
EG could be a potential therapeutic drug for the prevention of acute kidney injury caused by Stx2.
Impact
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For the first time, we have demonstrated that Eliglustat prevents Shiga toxin 2 cytotoxic effects on human renal epithelia, by reducing the expression of the toxin receptor globotriaosylceramide.
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The present work also shows that Eliglustat prevents Shiga toxin 2 effects on tubulogenesis of renal epithelial cells.
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Eliglustat, actually used for the treatment of patients with Gaucher’s disease, could be a therapeutic strategy to prevent the renal damage caused by Shiga toxin.
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Acknowledgements
We are grateful to the Pediatric Surgery team at the “Sección de Cirugía Pediátrica, Hospital General de Pediatría Pedro de Elizalde”, Buenos Aires, Argentina for providing kidney samples. We thank Natalia Beltramone, Flavia Sacerdoti, and Juan José Casal (IFIBIO-Houssay) for the technical assistance. This work was supported by grants to C.S. from the University of Buenos Aires (UBACYT20020160100078BA) and to C.I., M.M.A., and C.S. from the National Scientific and Technical Research Council (CONICET: PUE 0041).
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Each author has met the Pediatric Research authorship requirements. D.S.S., L.K.F.S., and C.S.: substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; A.B., C.I., M.M.A., and C.S.: drafting the article or revising it critically for important intellectual content; all authors approved the final manuscript version.
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Written informed consent from the next of kin or guardians on behalf of the children was obtained for use of kidney samples for research. The Ethics Committee of the Hospital General de Niños Pedro de Elizalde approved the use of human renal tissues for the development of primary cell cultures for research purposes.
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Sánchez, D.S., Fischer Sigel, L.K., Balestracci, A. et al. Eliglustat prevents Shiga toxin 2 cytotoxic effects in human renal tubular epithelial cells. Pediatr Res 91, 1121–1129 (2022). https://doi.org/10.1038/s41390-021-01622-3
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DOI: https://doi.org/10.1038/s41390-021-01622-3
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