Prevention of renal damage caused by Shiga toxin type 2: Action of Miglustat on human endothelial and epithelial cells.
Typical hemolytic uremic syndrome (HUS) is responsible for acute and chronic renal failure in children younger than 5 years old in Argentina. Renal damages have been associated with Shiga toxin type 1 and/or 2 (Stx1, Stx2) produced by Escherichia coli O157:H7, although strains expressing Stx2 are highly prevalent in Argentina. Human glomerular endothelial cells (HGEC) and proximal tubule epithelial cells are very Stx-sensitive since they express high levels of Stx receptor (Gb3). Nowadays, there is no available therapy to protect patients from acute toxin-mediated cellular injury. New strategies have been developed based on the Gb3 biosynthesis inhibition through blocking the enzyme glucosylceramide (GL1) synthase. We assayed the action of a GL1 inhibitor (Miglustat: MG), on the prevention of the renal damage induced by Stx2. HGEC primary cultures and HK-2 cell line were pre-treated with MG and then incubated with Stx2. HK- 2 and HGEC express Gb3 and MG was able to decrease the levels of this receptor. As a consequence, both types of cells were protected from Stx2 cytotoxicity and morphology damage. MG was able to avoid Stx2 effects in human renal cells and could be a feasible strategy to protect kidney tissues from the cytotoxic effects of Stx2 in vivo.
Laboratorio de Fisiopatogenia, Departamento de Fisiología, IFIBIO-Houssay UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Magalí C
MC
Girard
Laboratorio de Fisiopatogenia, Departamento de Fisiología, IFIBIO-Houssay UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Flavia
F
Sacerdoti
Laboratorio de Fisiopatogenia, Departamento de Fisiología, IFIBIO-Houssay UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Fulton P
FP
Rivera
Servicio de Pediatría [H.A.R.], Hospital Nacional Profesor Alejandro Posadas, BueCos Aires, Argentina.
Horacio A
HA
Repetto
Laboratorio de Fisiopatogenia, Departamento de Fisiología, IFIBIO-Houssay UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Cristina
C
Ibarra
Laboratorio de Fisiopatogenia, Departamento de Fisiología, IFIBIO-Houssay UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: mmamaral74@gmail.com.
María M
MM
Amaral
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D004727:Endothelium / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D022621:Shiga Toxin / Q000633:toxicity*
D017485:1-Deoxynojirimycin; D022621:Shiga Toxin; C059896:miglustat
Hemolytic uremic syndrome; Human glomerular endothelial cells; Immortalized human proximal tubule epithelial cells; Miglustat; Shiga toxin type 2