title: Ouabain protects against Shiga toxin-triggered apoptosis by reversing the imbalance between Bax and Bcl-xL.
abstract: Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-κB pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-κB antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Research Lab, Stockholm, Sweden.
authors.forename: Ievgeniia
authors.initials: I
authors.lastname: Burlaka
authors.forename: Xiao Li
authors.initials: XL
authors.lastname: Liu
authors.forename: Johan
authors.initials: J
authors.lastname: Rebetz
authors.forename: Ida
authors.initials: I
authors.lastname: Arvidsson
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Brismar
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
authors.forename: Anita
authors.initials: A
authors.lastname: Aperia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology; D053181:Caspase 8 / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D022641:Shiga Toxin 2 / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000502:physiology*; D051020:bcl-X Protein / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016328:NF-kappa B; D022641:Shiga Toxin 2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D010042:Ouabain; D053148:Caspase 3; D053181:Caspase 8; D000254:Sodium-Potassium-Exchanging ATPase