Ouabain Protects Human Renal Cells against the Cytotoxic Effects of Shiga Toxin Type 2 and Subtilase Cytotoxin

Abstract

Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx)-producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the world. STEC strains expressing Stx type 2 (Stx2) are responsible for the most severe cases of this pathology. Subtilase cytotoxin (SubAB) is another STEC virulence factor that may contribute to HUS pathogenesis. To date, neither a licensed vaccine nor effective therapy for HUS is available for humans. Considering that Ouabain (OUA) may prevent the apoptosis process, in this study we evaluated if OUA is able to avoid the damage caused by Stx2 and SubAB on human glomerular endothelial cells (HGEC) and the human proximal tubule epithelial cell (HK-2) line. HGEC and HK-2 were pretreated with OUA and then incubated with the toxins. OUA protected the HGEC viability from Stx2 and SubAB cytotoxic effects, and also prevented the HK-2 viability from Stx2 effects. The protective action of OUA on HGEC and HK-2 was associated with a decrease in apoptosis and an increase in cell proliferation. Our data provide evidence that OUA could be considered as a therapeutic strategy to avoid the renal damage that precedes HUS.

Computational Drug Repositioning for Ischemic Stroke: Neuroprotective Drug Discovery

“…Ouabain is used to treat congestive heart failure and to aid in the treatment of chronic atrial fibrillation. At present, studies have confirmed that ouabain has anti-inflammatory and antiapoptotic effects and can protect human renal cells [20]. However, there is no literature confirming its protective effect on the brain after ischemia.…”

Host response to the subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli

“…However, there is no effective vaccine or consensus therapy. Amaral et al 52 reported that ouabain, an Na + /K + ATPase inhibitor, inhibited apoptosis caused by Stx2 and SubAB. Our group found that diacylglycerol analogs (e.g.…”

Recent Advances in Shiga Toxin-Producing Escherichia coli Research in Latin America

“…They found that nanomolar concentrations of OUA protected HGEC viability from Stx2 and SubAB treatment and only protected HK-2 cells viability from Stx2 intoxication. These protective effects were associated with the prevention of apoptosis by increasing cell proliferation and suggested that OUA might have therapeutic use, preventing HUS-renal injury [42]. Further, the effects of Stx2 and SubAB on HGEC and HK-2 cells have been investigated by co-culturing both cells, resembling a human renal proximal tubule model of water absorption and cytotoxicity in the presence of Stx2 and SubAB.…”