Daiana S Sánchez1, Lilian K Fischer Sigel1, Alejandro Balestracci2, Cristina Ibarra3, María M Amaral3, Claudia Silberstein4. 1. Laboratorio de Investigaciones en Fisiología Renal, Facultad de Medicina, Departamento de Ciencias Fisiológicas, IFIBIO-Houssay CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina. 2. Servicio de Nefrología, Hospital General de Niños Pedro de Elizalde, Buenos Aires, Argentina. 3. Laboratorio de Fisiopatogenia, Facultad de Medicina, Departamento de Ciencias Fisiológicas, IFIBIO-Houssay CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina. 4. Laboratorio de Investigaciones en Fisiología Renal, Facultad de Medicina, Departamento de Ciencias Fisiológicas, IFIBIO-Houssay CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina. csilber@fmed.uba.ar.
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: 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. The present work also shows that Eliglustat prevents Shiga toxin 2 effects on tubulogenesis of renal epithelial cells. 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.
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: 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. The present work also shows that Eliglustat prevents Shiga toxin 2 effects on tubulogenesis of renal epithelial cells. 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.
Authors: Christina Frank; Dirk Werber; Jakob P Cramer; Mona Askar; Mirko Faber; Matthias an der Heiden; Helen Bernard; Angelika Fruth; Rita Prager; Anke Spode; Maria Wadl; Alexander Zoufaly; Sabine Jordan; Markus J Kemper; Per Follin; Luise Müller; Lisa A King; Bettina Rosner; Udo Buchholz; Klaus Stark; Gérard Krause Journal: N Engl J Med Date: 2011-06-22 Impact factor: 91.245
Authors: Lelis Meichtri; Elizabeth Miliwebsky; Andrea Gioffré; Isabel Chinen; Ariela Baschkier; Germán Chillemi; Beatriz E C Guth; Marcelo O Masana; Angel Cataldi; H Ricardo Rodríguez; Marta Rivas Journal: Int J Food Microbiol Date: 2004-11-01 Impact factor: 5.277