title: Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome.
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-alpha (TNF-alpha) 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-alpha. 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.
authors.affiliation: División Inmunología, IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina. gfernandez@hematologia.anm.edu.ar
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Fernández
authors.forename: Maroeska W M
authors.initials: MW
authors.lastname: Te Loo
authors.forename: Thea J A
authors.initials: TJ
authors.lastname: van der Velden
authors.forename: Lambert P W
authors.initials: LP
authors.lastname: van der Heuvel
authors.forename: Marina S
authors.initials: MS
authors.lastname: Palermo
authors.forename: Leo L A
authors.initials: LL
authors.lastname: Monnens
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000098:blood supply*; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007930:Leucine / Q000493:pharmacokinetics; D008833:Microcirculation; D022641:Shiga Toxin 2 / Q000494:pharmacology; D018180:Thrombomodulin / Q000378:metabolism*; D014316:Tritium
chemical_list: D018836:Inflammation Mediators; D022641:Shiga Toxin 2; D018180:Thrombomodulin; D014316:Tritium; D007930:Leucine