title: Shiga toxin 2-induced endoplasmic reticulum stress is minimized by activated protein C but does not correlate with lethal kidney injury.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. csleibow@bu.edu.
authors.forename: Caitlin S L
authors.initials: CS
authors.lastname: Parello
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. cmayer@bu.edu.
authors.forename: Chad L
authors.initials: CL
authors.lastname: Mayer
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. bclee@bu.edu.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. amoto@bu.edu.
authors.forename: Amanda
authors.initials: A
authors.lastname: Motomochi
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. kurosawa@bu.edu.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kurosawa
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA. dstearns@bu.edu.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stearns-Kurosawa
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D044082:Citrobacter rodentium; D004268:DNA-Binding Proteins / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D022641:Shiga Toxin 2 / Q000633:toxicity*; D051742:Transcription Factor CHOP / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; C494641:Dnajb1 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D011486:Protein C; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000071701:Regulatory Factor X Transcription Factors; D022641:Shiga Toxin 2; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP