Cardiotonic steroid-resistant α1-Na+,K+-ATPase rescues renal epithelial cells from the cytotoxic action of ouabain: evidence for a Na i + ,K i + -independent mechanism

Akimova, Olga A.; Tremblay, Johanne; Huysse, James W. Van; Hamet, Pavel; Orlov, Sergei N.

doi:10.1007/s10495-009-0429-4

Cited by 10 publications

(6 citation statements)

References 44 publications

(65 reference statements)

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“…5A). These results are consistent with previously reported attenuated sensitivity of intracellular Na + /K + homeostasis handling to ouabain in human HeLa and canine MDCK cells transfected with α1R-Na + ,K + -ATPase [35;36]. In mock-transfected cells, LDH release was detected at 24 hr after ouabain addition at the concentrations higher than 0.3 μM ouabain, and was increased by ~ 6-fold in the presence of 3 μM ouabain (Fig.…”

Section: Resultssupporting

confidence: 93%

Critical role of the α1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain

et al. 2015

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SUMMARY In rodents, ubiquitous α1-Na+,K+-ATPase is inhibited by ouabain and other cardiotonic steroids (CTS) at ~103-fold higher concentrations than those effective in other mammals. To examine the specific roles of the CTS-sensitive α1S- and CTS-resistant α1R-Na+,K+-ATPase isoforms, we compared the effects of ouabain on intracellular Na+ and K+ content, cell survival, and mitogen-activated protein kinases (MAPK) in human and rat vascular smooth muscle cells (HASMC and RASMC), human and rat endothelial cells (HUVEC and RAEC), and human and rat brain astrocytes. Six-hour exposure of HASMC and HUVEC to 3 μM ouabain dramatically increased the intracellular [Na+]/[K+] ratio to the same extend as in RASMC and RAEC treated with 3,000 μM ouabain. In 24, 3 μM ouabain triggered the death of all types of human cells used in this study. Unlike human cells, we did not detect any effect of 3,000-5,000 μM ouabain on the survival of rat cells, or smooth muscle cells from mouse aorta (MASMC). Unlike in the wild-type α1R/R mouse, ouabain triggered death of MASMC from α1S/S mouse expressing human α1-Na+,K+-ATPase. Furthermore, transfection of HUVEC with rat α1R-Na+,K+-ATPase protected them from the ouabain-induced death. In HUVEC, ouabain led to phosphorylation of p38 MAPK, whereas in RAEC it stimulated phosphorylation of ERK1/2. Overall, our results, demonstrate that the drastic differences in cytotoxic action of ouabain on human and rodent cells are caused by unique features of α1S/α1R-Na+,K+-ATPase, rather than by any downstream CTS-sensitive/resistant components of the cell death machinery.

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Section: Resultssupporting

confidence: 93%

Critical role of the α1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain

et al. 2015

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“…Six-hour treatment of ␣1R-cells with 1,000 M ouabain produced similar increment of the [Na ϩ ] i /[K ϩ ] i ratio detected in mock-transfected cells treated with 3 M ouabain. However, in contrast to the massive death of mock-transfected cells exposed to 3 M ouabain, ␣1R-cells survived after 24-h incubation with 1,000 M ouabain (5). As a working hypothesis, we proposed that the ␣1R subunit rescues cells from the cytotoxic action of CTS independently of inhibition of Na ϩ -K ϩ -ATPase-mediated Na ϩ and K ϩ fluxes.…”

Section: [Na ϩ ] I /[K ϩ ] I -Independent Death Signaling Triggered Bmentioning

confidence: 93%

Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression

Orlov

Platonova

Hamet

et al. 2013

American Journal of Physiology-Cell Physiology

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Cell death is accompanied by the dissipation of electrochemical gradients of monovalent ions across the plasma membrane that, in turn, affects cell volume via modulation of intracellular osmolyte content. In numerous cell types, apoptotic and necrotic stimuli caused cell shrinkage and swelling, respectively. Thermodynamics predicts a cell type-specific rather than an ubiquitous impact of monovalent ion transporters on volume perturbations in dying cells, suggesting their diverse roles in the cell death machinery. Indeed, recent data showed that apoptotic collapse may occur in the absence of cell volume changes and even follow cell swelling rather than shrinkage. Moreover, side-by-side with cell volume adjustment, monovalent ion transporters contribute to cell death machinery engagement independently of volume regulation via cell type-specific signaling pathways. Thus, inhibition of Na(+)-K(+)-ATPase by cardiotonic steroids (CTS) rescues rat vascular smooth muscle cells from apoptosis via a novel Na(+)i-K(+)i-mediated, Ca(2+)i-independent mechanism of excitation-transcription coupling. In contrast, CTS kill renal epithelial cells independently of Na(+)-K(+)-ATPase inhibition and increased [Na(+)]i/[K(+)]i ratio. The molecular origin of [Na(+)]i/[K(+)]i sensors involved in the inhibition of apoptosis as well as upstream intermediates of Na(+)i/K(+)i-independent death signaling triggered by CTS remain unknown.

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“…Second, propagation of the death signal triggered by interactions of CTS with the Na + ,K + -ATPase occurs on the background of the elevated [Na + ] i /[K + ] i ratio ( Figure 2 , pathway S4). To further examine these hypotheses, we transfected MDCK cells expressing α1S-Na + ,K + -ATPase with rodent CTS-resistant α1R-Na + ,K + -ATPase [ 110 ]. Six-hour treatment of α1R-cells with 1000 μM ouabain produced a similar increment of the [Na + ] i /[K + ] i ratio detected in mock-transfected cells treated with 3 μM ouabain.…”

Section: Evidence For Na + I K mentioning

confidence: 99%

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

et al. 2017

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Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na+ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na+i/K+i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death. It was also shown that CTS trigger diverse signaling cascades via conformational transitions of the Na+,K+-ATPase α-subunit that, in turn, results in the activation of membrane-associated non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase and the inositol 1,4,5-triphosphate receptor. These findings allowed researchers to propose that endogenous CTS might be considered as a novel class of steroid hormones. We focus our review on the analysis of the relative impact Na+i,K+i-mediated and -independent pathways in cellular responses evoked by CTS.

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Cardiotonic steroid-resistant α1-Na+,K+-ATPase rescues renal epithelial cells from the cytotoxic action of ouabain: evidence for a Na i + ,K i + -independent mechanism

Cited by 10 publications

References 44 publications

Critical role of the α1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain

Critical role of the α1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain

Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

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