title: Lack of the lectin-like domain of thrombomodulin worsens Shiga toxin-associated hemolytic uremic syndrome in mice.
abstract: Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TM(wt/wt)) and mice that lack the lectin-like domain of TM (TM(LeD/LeD)), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TM(LeD/LeD) mice exhibited more severe thrombocytopenia and renal dysfunction than TM(wt/wt) mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TM(LeD/LeD) than in TM(wt/wt) mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TM(LeD/LeD) mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TM(LeD/LeD) mice with HUS had a higher mortality rate than TM(wt/wt) mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Parco Scientifico Tecnologico Kilometro Rosso, 24126 Bergamo, Italy. carlamaria.zoja@marionegri.it
authors.forename: Carlamaria
authors.initials: C
authors.lastname: Zoja
authors.forename: Monica
authors.initials: M
authors.lastname: Locatelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Pagani
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Cristina
authors.initials: C
authors.lastname: Zanchi
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
mesh_terms: D000818:Animals; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D037102:Lectins / Q000172:deficiency*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000235:genetics; D012720:Severity of Illness Index; D022621:Shiga Toxin / Q000008:administration & dosage*; D018180:Thrombomodulin / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D037102:Lectins; C569169:THBD protein, mouse; D018180:Thrombomodulin; D022621:Shiga Toxin