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1 Medicine/Kidney Disease Program, University of Louisville, Louisville, Kentucky, United States
2 Ophthalmology, University of Louisville, Louisville, Kentucky, United States
3 Medicine, University of Louisville, Louisville, Kentucky, United States
4 Opthalmology and Pharmacology, Univ. Louisville Sch. Medicine, Louisville, Kentucky, United States
* To whom correspondence should be addressed. E-mail: syed.khundmiri{at}kdp.louisville.edu.
Cardiotonic glycosides like ouabain inhibit Na+-K+ ATPase. Recent evidence suggests that low concentrations of ouabain alter cell growth. The effect of ouabain on Akt phosphorylation and rate of cell proliferation in opossum kidney (OK) proximal tubule cells was studied. Cells exposed to 10nM ouabain displayed increased Akt Ser473 phosphorylation as evidenced by an increase in phospho-Akt Ser473 band density. Ouabain-stimulated Akt Ser473 phosphorylation was inhibited by pretreatment with PI3K inhibitors (LY294002 and wortmannin), PLC inhibitor (edelfosine), and Akt inhibitor. Moreover, ouabain-mediated Akt Ser473 phosphorylation was suppressed by removal of extracellular calcium (EGTA) or when intracellular calcium was buffered by BAPTA-AM. Inhibitor of calcium store release (TMB-8) and inhibitor of calcium entry via store operated calcium channels (SKF96365) also suppressed ouabain mediated Akt Ser473 phosphorylation. In Fura-2 loaded cells, 10nM ouabain increased capacitative calcium entry (CCE). 10nM ouabain did not significantly alter baseline cytoplasmic calcium concentration in control cells. However, treatment with 10nM ouabain caused a significantly higher ATP-mediated calcium store release. After 24h, 10nM ouabain increased the rate of cell proliferation. Akt inhibitor, BAPTA, SKF, and CPA suppressed the increase in the rate of cell proliferation caused by 10nM ouabain. Ouabain at 10nM concentration caused detectable increase in 86Rb uptake but did not significantly alter Na+-K+ ATPase (ouabain-sensitive pNPPase) activity in crude membranes or cell sodium content. Taken together, the results point to a role for CCE and Akt phosphorylation in response to low concentrations of ouabain that increase the rate of cell proliferation without inhibiting Na+-K+ ATPase-mediated ion transport.
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