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Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction

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Abstract

Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli O157:H7 has become a global threat to public health, as a primary cause of a worldwide spread of hemorrhagic colitis complicated by diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure that mainly affects early childhood. Endothelial dysfunction has been recognized as the trigger event in the development of microangiopathic processes. Endothelial cells, mainly those located in the renal microvasculature, are primary targets of the toxic effects of Stx1 and 2. Stxs bound to their specific globotriaosylceramide (Gb3Cer) receptor on the cell surface trigger a cascade of signaling events, involving NF-κB activation, that induce expression of genes encoding for adhesion molecules and chemokines, and culminate in the adhesion of leukocytes to endothelial cells, thereby increasing the endothelial susceptibility to leukocyte-mediated injury. Activated endothelial cells in response to Stxs lose the normal thromboresistance phenotype and become thrombogenic, initiating microvascular thrombus formation. Evidence is emerging that complement activation in response to Stxs favors platelet thrombus formation on endothelial cells, which may play a role in amplifying the inflammation–thrombosis circuit in Stx-associated HUS.

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Acknowledgements

The authors thank Prof. Giuseppe Remuzzi for reviewing the manuscript and Dr. Antonella Piccinelli for helping in figure preparation. Manuela Passera helped to prepare the manuscript.

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  1. Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125, Bergamo, Italy

    Carla Zoja, Simona Buelli & Marina Morigi

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  1. Carla Zoja
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  2. Simona Buelli
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  3. Marina Morigi
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Correspondence to Carla Zoja.

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Zoja, C., Buelli, S. & Morigi, M. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol 25, 2231–2240 (2010). https://doi.org/10.1007/s00467-010-1522-1

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  • DOI: https://doi.org/10.1007/s00467-010-1522-1

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