Toxins 2015, 7(1), 170-186; doi:10.3390/toxins7010170
Shiga Toxin 2-Induced Endoplasmic Reticulum Stress Is Minimized by Activated Protein C but Does Not Correlate with Lethal Kidney Injury
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA
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Author to whom correspondence should be addressed.
Academic Editor: Vernon L. Tesh
Received: 17 November 2014 / Revised: 22 December 2014 / Accepted: 14 January 2015 / Published: 20 January 2015
(This article belongs to the Section Animal Venoms)
Abstract
Enterohemorrhagic Escherichia coli produce ribotoxic Shiga toxins (Stx), which are responsible for kidney injury and development of hemolytic uremic syndrome. The endoplasmic reticulum (ER) stress response is hypothesized to induce apoptosis contributing to organ injury; however, this process has been described only in vitro. ER stress marker transcripts of spliced XBP1 (1.78-fold), HSP40 (4.45-fold) and CHOP (7.69-fold) were up-regulated early in kidneys of Stx2 challenged mice compared to saline controls. Anti-apoptotic Bcl2 decreased (−2.41-fold vs. saline) and pro-apoptotic DR5 increased (6.38-fold vs. saline) at later time points. Cytoprotective activated protein C (APC) reduced early CHOP expression (−3.3-fold vs. untreated), increased later Bcl2 expression (5.8-fold vs. untreated), and had early effects on survival but did not alter DR5 expression. Changes in kidney ER stress and apoptotic marker transcripts were observed in Stx2-producing C. rodentium challenged mice compared to mice infected with a non-toxigenic control strain. CHOP (4.14-fold) and DR5 (2.81-fold) were increased and Bcl2 (−1.65-fold) was decreased. APC reduced CHOP expression and increased Bcl2 expression, but did not alter mortality. These data indicate that Stx2 induces renal ER stress and apoptosis in murine models of Stx2-induced kidney injury, but decreasing these processes alone was not sufficient to alter survival outcome. View Full-TextKeywords:
Shiga toxin; endoplasmic reticulum stress; apoptosis; kidney injury; enterohemorrhagic Escherichia coli; hemolytic uremic syndrome
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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MDPI and ACS Style
Parello, C.S.L.; Mayer, C.L.; Lee, B.C.; Motomochi, A.; Kurosawa, S.; Stearns-Kurosawa, D.J. Shiga Toxin 2-Induced Endoplasmic Reticulum Stress Is Minimized by Activated Protein C but Does Not Correlate with Lethal Kidney Injury. Toxins 2015, 7, 170-186.
