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Infection and Immunity, March 2009, p. 959-969, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.00679-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium{triangledown}

Mitchell A. Psotka,1 Fumiko Obata,1 Glynis L. Kolling,1 Lisa K. Gross,1 Moin A. Saleem,2,3 Simon C. Satchell,2 Peter W. Mathieson,2 and Tom G. Obrig1*

Department of Internal Medicine, Division of Nephrology, University of Virginia, Charlottesville, Virginia,1 Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom,2 Children's Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom3

Received 30 May 2008/ Returned for modification 26 August 2008/ Accepted 29 December 2008

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 (Gb3) 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 Gb3 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.

* Corresponding author. Present address: Department of Microbiology and Immunology, University of Maryland, Baltimore, 660 Redwood St., Baltimore, MD 21201. Phone: (410) 706-6917. Fax: (410) 706-2129. E-mail: tobrig{at}som.umaryland.edu

{triangledown} Published ahead of print on 5 January 2009.

Editor: V. J. DiRita

Infection and Immunity, March 2009, p. 959-969, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.00679-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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