Shiga toxin 2 targets the murine renal collecting duct epithelium.
Hemolytic-uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli infection is a leading cause of pediatric acute renal failure. Bacterial toxins produced in the gut enter the circulation and cause a systemic toxemia and targeted cell damage. It had been previously shown that injection of Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS) caused signs and symptoms of HUS in mice, but the mechanism leading to renal failure remained uncharacterized. The current study elucidated that murine cells of the glomerular filtration barrier were unresponsive to Stx2 because they lacked the receptor glycosphingolipid globotriaosylceramide (Gb(3)) in vitro and in vivo. In contrast to the analogous human cells, Stx2 did not alter inflammatory kinase activity, cytokine release, or cell viability of the murine glomerular cells. However, murine renal cortical and medullary tubular cells expressed Gb(3) and responded to Stx2 by undergoing apoptosis. Stx2-induced loss of functioning collecting ducts in vivo caused production of increased dilute urine, resulted in dehydration, and contributed to renal failure. Stx2-mediated renal dysfunction was ameliorated by administration of the nonselective caspase inhibitor Q-VD-OPH in vivo. Stx2 therefore targets the murine collecting duct, and this Stx2-induced injury can be blocked by inhibitors of apoptosis in vivo.
Psotka
Mitchell A
MA
Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 21201, USA.
Obata
Fumiko
F
Kolling
Glynis L
GL
Gross
Lisa K
LK
Saleem
Moin A
MA
Satchell
Simon C
SC
Mathieson
Peter W
PW
Obrig
Tom G
TG
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007685:Kidney Tubules, Collecting / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D022641:Shiga Toxin 2 / Q000276:immunology / Q000378:metabolism*; D014471:Umbilical Veins
D015295:Antigens, Tumor-Associated, Carbohydrate; C472766:Gb3 antigen; D008070:Lipopolysaccharides; D022641:Shiga Toxin 2