Abstract
Shiga toxin (Stx), produced by Escherichia coli, is the main pathogenic factor of diarrhea-associated hemolytic uremic syndrome (HUS), which is characterized by the obstruction of renal microvasculature by platelet-fibrin thrombi. It is well known that the oxidative imbalance generated by Stx induces platelet activation, contributing to thrombus formation. Moreover, activated platelets release soluble CD40 ligand (sCD40L), which in turn contributes to oxidative imbalance, triggering the release of reactive oxidative species (ROS) on various cellular types. The aim of this work was to determine if the interaction between the oxidative response and platelet-derived sCD40L, as consequence of Stx-induced endothelium damage, participates in the pathogenic mechanism during HUS. Activated human glomerular endothelial cells (HGEC) by Stx2 induced platelets to adhere to them. Although platelet adhesion did not contribute to endothelial damage, high levels of sCD40L were released to the medium. The release of sCD40L by activated platelets was inhibited by antioxidant treatment. Furthermore, we found increased levels of sCD40L in plasma from HUS patients, which were also able to trigger the respiratory burst in monocytes in a sCD40L-dependent manner. Thus, we concluded that platelet-derived sCD40L and the oxidative response are reciprocally stimulated during Stx2-associated HUS. This process may contribute to the evolution of glomerular occlusion and the microangiopathic lesions.
Highlights
Shiga toxin (Stx)-producing Escherichia coli (STEC) is associated with the development of hemolytic uremic syndrome (HUS), which is characterized by hemorrhagic diarrhea followed by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [1].After ingestion, STEC colonize the intestine and produce Stx that translocates across the intestinal epithelium [2]
We investigated the effects of Stx2 and oxidative stress on renal microvasculature, platelet adhesion, and soluble CD40 ligand (sCD40L) release in order to identify a novel mechanism contributing to thrombotic microangiopathy
No significant changes were observed with 0.1 ng/mL Stx2, 1 ng/mL Stx2 induced a significant toxicity on human glomerular endothelial cells (HGEC) as it was demonstrated by a decreased uptake of the vital dye neutral red (Figure 1A,B)
Summary
Shiga toxin (Stx)-producing Escherichia coli (STEC) is associated with the development of hemolytic uremic syndrome (HUS), which is characterized by hemorrhagic diarrhea followed by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [1].After ingestion, STEC colonize the intestine and produce Stx that translocates across the intestinal epithelium [2]. Shiga toxin (Stx)-producing Escherichia coli (STEC) is associated with the development of hemolytic uremic syndrome (HUS), which is characterized by hemorrhagic diarrhea followed by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [1]. Once Stx enters into bloodstream, it binds to its specific globotriaosylceramide (Gb3) receptor, which is present on microvascular endothelial cells and epithelial cells of target organs and monocytes. Microvascular endothelial cells, mostly of renal glomeruli, become activated in response to Stx and lose their anti-thrombogenic properties. This leads to the upregulation of adhesive molecules, such as vitronectin receptor, PECAM-1, and P-selectin on endothelial surface that mediate platelet adhesion and thrombi formation [6]. Platelet adhesion and subsequent aggregation contribute to the formation of platelet-fibrin thrombi characteristic of the thrombotic microangiopathy during Stx-associated HUS [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
