Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement.

Abstract

Shiga toxin (Stx)-producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complement activation, generating C3a responsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated. Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and α-actinin-4. Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocyte dysregulation. Similarly, pretreatment with a C3a receptor antagonist limited podocyte loss and changes in ILK, Snail, and α-actinin-4 expression. In cultured podocytes, treatment with C3a reduced α-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3a promotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS.

• Authors: Monica Locatelli, Simona Buelli, Anna Pezzotta, Daniela Corna, Luca Perico, Susanna Tomasoni, Daniela Rottoli, Paola Rizzo, Debora Conti, Joshua M Thurman, Giuseppe Remuzzi, Carlamaria Zoja, Marina Morigi
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 25 Issue 8 Pg. 1786-98 (Aug 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24578132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Lipopolysaccharides
• Shiga Toxin 2
• Complement C3a
• integrin-linked kinase
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Culture Techniques
• Complement C3a (metabolism)
• Complement Pathway, Alternative (drug effects)
• Disease Models, Animal
• Hemolytic-Uremic Syndrome (etiology, metabolism, pathology)
• Humans
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Podocytes (drug effects, metabolism, pathology)
• Protein Serine-Threonine Kinases (metabolism)
• Shiga Toxin 2 (pharmacology)
• Signal Transduction