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Investigation of mechanism of p38 MAPK activation in renal epithelial cell from distal tubules triggered by cardiotonic steroids

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Abstract

Ouabain and other cardiotonic steroids (CTS) kill renal epithelial cells from distal tubules (C7-MDCK) via interaction with Na,K-ATPase but independently of inhibition of Na,K-ATPase-mediated ion fluxes. Recently, we demonstrated that modest intracellular acidification and inhibition of p38 MAPK suppress death of C7-MDCK cells triggered by ouabain. In the present study we investigate the mechanism of p38 MAPK activation in renal epithelial cell from distal tubules evoked by cardiotonic steroids. Using Na+/K+ ionophores (monensin, nigericin) and media with different content of monovalent cations, we revealed that p38 MAPK phosphorylation in ouabain-treated renal epithelial cells is not caused by Na,K-ATPase inhibition and inversion of the [Na+]i/[K+]i ratio. We also demonstrated that attenuation of pH from 7.45 to 6.75 did not alter the level of p38 MAPK phosphorylation observed in ouabain-treated cells. Inhibitors of PKA, PKC, and PKG as well as protein phosphatases were unable to abolish p38 MAPK activation triggered by ouabain. Using phosphotyrosine antibodies we did not detect any effect of ouabain on activation of tyrosine kinases. Thus, our results show that activation of p38 MAPK and cytotoxic action of CTS are independent of intracellular Na+, K+, and H+ concentrations. The molecular origin of intermediates of death signaling induced by CTS via conformation changes of Na,K-ATPase with following activation of p38 MAPK should be examined further.

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Abbreviations

CTS:

cardiotonic steroids

[K+]i :

intracellular concentration of potassium ions

MAPK:

mitogen-activated protein kinase

[Na+]i :

intracellular concentration of sodium ions

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    O. A. Akimova, O. D. Lopina, A. M. Rubtsov & S. N. Orlov

  2. Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, ul. Baltiiskaya 8, 125315, Moscow, Russia

    O. A. Akimova & S. N. Orlov

  3. Centre de Recherche, Centre Hospitalier de l’Universite de Montreal (CHUM) — Technopole-Angus, 2901 Rachel Est, Montreal, Canada, H1W 4A4

    O. A. Akimova, P. Hamet & S. N. Orlov

Authors
  1. O. A. Akimova
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  2. O. D. Lopina
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  3. A. M. Rubtsov
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  4. P. Hamet
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  5. S. N. Orlov
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Correspondence to O. A. Akimova.

Additional information

Published in Russian in Biokhimiya, 2010, Vol. 75, No. 8, pp. 1070–1078.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM10-058, May 30, 2010.

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Akimova, O.A., Lopina, O.D., Rubtsov, A.M. et al. Investigation of mechanism of p38 MAPK activation in renal epithelial cell from distal tubules triggered by cardiotonic steroids. Biochemistry Moscow 75, 971–978 (2010). https://doi.org/10.1134/S0006297910080043

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  • DOI: https://doi.org/10.1134/S0006297910080043

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