Shiga toxin triggers endothelial and podocyte injury: the role of complement activation

Abstract

Shiga toxin (Stx)-producing Escherichia coli (STEC) is the offending agent in post-diarrhea-associated hemolytic uremic syndrome (HUS), a disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney failure, with thrombi occluding the renal microvasculature. Endothelial dysfunction has been recognized as the trigger event in the development of microangiopathic processes. Glomerular endothelial cells are susceptible to the toxic effects of Stxs that, via nuclear factor kappa B (NF-κB) activation, induce the expression of genes encoding for adhesion molecules and chemokines, culminating in leukocyte adhesion and platelet thrombus formation on the activated endothelium. Complement activation via the alternative pathway has been seen in patients during the acute phase of STEC-associated HUS. Experimental evidence has highlighted the role of complement proteins in driving glomerular endothelium toward a thrombogenic phenotype. At the glomerular level, podocytes are also an important target of Stx-induced complement activation. Glomerular injury as a consequence of podocyte dysfunction and loss is thus a mechanism that might affect long-term renal outcomes in the disease. New approaches to targeting the complement system may be useful therapeutic options for patients with STEC-HUS.

Shiga-Toxin E. coli Hemolytic Uremic Syndrome: Review of Management and Long-term Outcome

“…Shiga-toxin activates complement and binds to factor H (an inhibitor to the alternative pathway) with a reduction in co-factor responsiveness but no impact on functional ability [13]. More recently, activation of C3 and C3a deposition in the glomerular basement membrane has been associated with podocyte dysfunction, with downregulation of nephrin and other functional proteins [14].…”

“…The combination of clinical and laboratory findings supporting a role for complement, and the striking impact of complement blockade in the treatment of the related inherited condition, atypical HUS (aHUS), has led to therapeutic efforts targeting complement in the treatment of STEC-HUS [11,12,[14][15][16][17].…”

Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

“…Indeed, elevated plasma levels of complement activation biomarkers were documented at the acute phase of post diarrheal/typical/Shiga toxin HUS (6)(7)(8)(9)(10)(11). In vitro studies and animal models experiments demonstrated that Shiga toxin generates a cascade of endothelial/podocyte injury, complement activation, expression of chemokines and adhesion molecules, neutrophil activation, and thrombus formation (7,(12)(13)(14)(15)(16)(17)(18). The hypothesis of a genetic predisposition in Shiga toxin-associated HUS emerged in 2008, with the publication of a case of a 4-year-old girl with Shiga toxin-associated HUS, who died with a multiorgan failure syndrome and was found to carry pathogenic membrane cofactor protein variant (19).…”

Cerebral sinovenous thrombosis in pediatric hemolytic uremic syndrome

“…At its core, HUS is a disorder of microangiopathy precipitated by endothelial injury leading to inflammation and formation of thrombi. While this provides a theoretical basis for development of thrombotic complications in large vessels, it does not explain why thrombotic complications in HUS generally tend to occur in the microvasculature rather than large vessels 1,7 …”

“…Hemolytic uremic syndrome (HUS) is characterized by acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia, and it is most commonly caused by Shiga toxin–producing Escherichia coli 1 . Although the clinical effects of the disease on the microvasculature are primarily manifest by renal involvement, Shiga toxin–induced endothelial damage and elevations of prothrombotic factors may theoretically lead to a generalized predisposition to thrombosis.…”