Pediatric Nephrology

, Volume 18, Issue 10, pp 1066–1068

Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome

  • Gabriela C. Fernández
  • Maroeska W. M. Te Loo
  • Thea J. A. van der Velden
  • Lambert P. W. van der Heuvel
  • Marina S. Palermo
  • Leo L. A. Monnens
Brief Report

Abstract

The typical form of hemolytic uremic syndrome (D+HUS) is a thrombotic microangiopathy that causes acute renal failure in children. The etiology of this disease is a toxin called Shiga-like toxin (Stx), present in certain strains of gram-negative bacteria. Vascular endothelial cell (EC) injury appears to be central in the pathogenesis of D+HUS. Thrombomodulin (TM) is a glycoprotein present in EC with anti-thrombogenic properties. The objective of this study was to investigate the effects of Stx on the surface expression of TM in EC using an in vitro culture of human glomerular microvascular endothelial cells. We also evaluated other inflammatory mediators [tumor necrosis factor-α (TNF-α) and lipopolysaccharide], which are known to increase Stx receptor expression and are potentially involved in the pathogenesis of D+HUS. Stx2 induced a significant decrease of TM expression in this cell type after pre-incubation with TNF-α. This decrease could not be attributed to the inhibition of protein synthesis only, as cycloheximide, another inhibitor of protein synthesis, did not affect TM surface expression. These results suggest that the Stx2-induced decrease of TM expression in glomerular EC might contribute to the local procoagulant state present in D+HUS.

Keywords

Thrombomodulin Hemolytic uremic syndrome Glomerular endothelial cells Tumor necrosis factor-α Shiga-like toxin 

References

  1. 1.
    Remuzzi G, Ruggenenti P (1995) The hemolytic uremic syndrome. Kidney Int 48:2–19PubMedGoogle Scholar
  2. 2.
    Esmon CT (1995) Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 9:946–955PubMedGoogle Scholar
  3. 3.
    He CJ, Kanfer A (1992) Quantification and modulation of thrombomodulin activity in isolated rat and human glomeruli. Kidney Int 41:1170–1174PubMedGoogle Scholar
  4. 4.
    Weiler-Guettler H, Christie PD, Beeler DL, Healy AM, Hancock WW, Rayburn H, Edelberg JM, Rosenberg RD (1998) A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest 101:1983–1991PubMedGoogle Scholar
  5. 5.
    Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K (1996) Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation. Am J Physiol 271:L470–L475PubMedGoogle Scholar
  6. 6.
    Setten PA van, Hinsbergh VW van, Velden TJ van der, Kar NC van de, Vermeer M, Mahan JD, Assmann KJ, Heuvel LP van der, Monnens LA (1997) Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells. Kidney Int 51:1245–1256PubMedGoogle Scholar
  7. 7.
    Raife TJ, Demetroulis EM, Lentz SR (1996) Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-alpha: differential responses in keratinocytes and endothelial cells. Blood 88:2043–2049PubMedGoogle Scholar
  8. 8.
    Harel Y, Silva M, Giroir B, Weinberg A, Cleary TB, Beutler B (1993) A reporter transgene indicates renal-specific induction of tumor necrosis factor (TNF) by shiga-like toxin. Possible involvement of TNF in hemolytic uremic syndrome. J Clin Invest 92:2110–2116PubMedGoogle Scholar
  9. 9.
    Takano S, Kimura S, Ohdama S, Aoki N (1990) Plasma thrombomodulin in health and diseases. Blood 76:2024–2029PubMedGoogle Scholar
  10. 10.
    Nevard CH, Blann AD, Jurd KM, Haycock GB, Hunt BJ (1999) Markers of endothelial cell activation and injury in childhood haemolytic uraemic syndrome. Pediatr Nephrol 13:487–492CrossRefPubMedGoogle Scholar
  11. 11.
    Ozdemir S, Besbas N, Saatci U, Bakkaloglu A (1996) Plasma thrombomodulin concentrations in uraemic children. Nephrol Dial Transplant 11:2369–2370PubMedGoogle Scholar
  12. 12.
    Campbell WD, Lazoura E, Okada N, Okada H (2002) Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol 46:131–134PubMedGoogle Scholar

Copyright information

© IPNA 2003

Authors and Affiliations

  • Gabriela C. Fernández
    • 1
    • 3
  • Maroeska W. M. Te Loo
    • 2
  • Thea J. A. van der Velden
    • 2
  • Lambert P. W. van der Heuvel
    • 2
  • Marina S. Palermo
    • 1
  • Leo L. A. Monnens
    • 2
  1. 1.División Inmunología, IIHEMAAcademia Nacional de MedicinaBuenos AiresArgentina
  2. 2.Department of NephrologyUniversity Medical Center St. RadboudNijmegenThe Netherlands
  3. 3.Academia Nacional de MedicinaBuenos AiresArgentina

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