Ouabain Protects against Shiga Toxin-Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL
2013 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, Vol. 24, no 9, 1413-1423 p.Article in journal (Refereed) Published
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-B 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-B 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.
Place, publisher, year, edition, pages
2013. Vol. 24, no 9, 1413-1423 p.
Hemolytic-Uremic Syndrome, Nf-Kappa-B, Calcium Oscillations, Family-Members, Cell-Death, Receptor, Disease, Na, K-Atpase, Kidney, Progression
Urology and Nephrology
IdentifiersURN: urn:nbn:se:kth:diva-133653DOI: 10.1681/ASN.2012101044ISI: 000325092900013ScopusID: 2-s2.0-84884297830OAI: oai:DiVA.org:kth-133653DiVA: diva2:663301
FunderSwedish Research Council, K2011-54X-03644-40-6 K2010-65X-14008-10-3Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
QC 201311112013-11-112013-11-082013-12-04Bibliographically approved