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Inhibition of water absorption in human proximal tubular epithelial cells in response to Shiga toxin-2

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Abstract

Postdiarrhea hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children in Argentina. It is well established that Shiga toxin type 2 (Stx2) causes direct damage to glomerular endothelial cells and tubular epithelial cells, leading to a reduction in the water handling capacity of the kidney. In this study, we demonstrate that Stx2 and its B subunit (Stx2B) were able to inhibit water absorption across human renal tubular epithelial cell (HRTEC) monolayers without altering the short circuit current and the 3H-mannitol permeability. Quantitative evaluation of 14C-inulin transport across HRTEC monolayers showed a similar transport rate both before and after HRTEC treatment with Stx2 that confirmed the integrity of the paracellular pathway. Furthermore, Stx2 produced significant protein synthesis inhibition of HRTEC at concentrations as low as 0.001 ng/ml and 1 h of incubation, whereas Stx2B did not modify it at concentrations as high as 10,000 ng/ml and 6 h of incubation. Our findings suggest that whereas the action of Stx2 appears to be caused mainly by the inhibition of protein synthesis mediated by the A subunit, the binding of Stx2B subunit to the Gb3 receptor may affect the membrane mechanisms related to water absorption. We speculate that inhibition of water absorption may occur in proximal tubular cells in vivo in response to Stx2 and may contribute to the early event of HUS pathogenesis.

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Acknowledgements

We are grateful to Dr. Osvaldo N. Mazza, Unidad de Urologia, Hospital de Clínicas “José de San Martín”, for provision of human kidney fragments; and Eugene Chang, University of Chicago, for providing the purified Ig G antibody against NHE3. This work was supported by grants to Cristina Ibarra from Universidad de Buenos Aires, CONICET and ANPCYT.

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Authors and Affiliations

  1. Laboratorio de Fisiopatogenia, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Claudia Silberstein, Virginia Pistone Creydt, Elizabeth Gerhardt, Pablo Núñez & Cristina Ibarra

  2. Paraguay 2155, 7mo piso, 1121, Buenos Aires, Argentina

    Cristina Ibarra

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  1. Claudia Silberstein
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  2. Virginia Pistone Creydt
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  3. Elizabeth Gerhardt
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  4. Pablo Núñez
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  5. Cristina Ibarra
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Correspondence to Cristina Ibarra.

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Silberstein, C., Pistone Creydt, V., Gerhardt, E. et al. Inhibition of water absorption in human proximal tubular epithelial cells in response to Shiga toxin-2. Pediatr Nephrol 23, 1981–1990 (2008). https://doi.org/10.1007/s00467-008-0896-9

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  • DOI: https://doi.org/10.1007/s00467-008-0896-9

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