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首页> 外文期刊>American Journal of Physiology >Ouabain stimulates protein kinase B (Akt) phosphorylation in opossum kidney proximal tubule cells through an ERK-dependent pathway.
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Ouabain stimulates protein kinase B (Akt) phosphorylation in opossum kidney proximal tubule cells through an ERK-dependent pathway.

机译：哇巴因通过ERK依赖性途径刺激负鼠肾近端小管细胞中的蛋白激酶B（Akt）磷酸化。

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摘要

Endogenous cardiotonic glycosides bind to the inhibitory binding site of the plasma membrane sodium pump (Na(+)/K(+)-ATPase). Plasma levels of endogenous cardiotonic glycosides increase in several disease states, such as essential hypertension and uremia. Low concentrations of ouabain, which do not inhibit Na(+)/K(+)-ATPase, induce cell proliferation. The mechanisms of ouabain-mediated response remain unclear. Recently, we demonstrated that in opossum kidney (OK) proximal tubular cells, low concentrations of ouabain induce cell proliferation through phosphorylation of protein kinase B (Akt) in a calcium-dependent manner. In the present study, we identified ERK as an upstream kinase regulating Akt activation in ouabain-stimulated cells. Furthermore, we provide evidence that low concentrations of ouabain stimulate Na(+)/K(+)-ATPase-mediated (86)Rb uptake in an Akt-, ERK-, and Src kinase-dependent manner. Ouabain-mediated ERK phosphorylation was inhibited by blockade of intracellular calcium release, calcium entry, tyrosine kinases, and phospholipase C. Pharmacological inhibition of phosphoinositide-3 kinase and Akt failed to inhibit ouabain-stimulated ERK phosphorylation. Ouabain-mediated Akt phosphorylation was inhibited by U0126, a MEK/ERK inhibitor, suggesting that ouabain-mediated Akt phosphorylation is dependent on ERK. In an in vitro kinase assay, active recombinant ERK phosphorylated recombinant Akt on Ser(473). Moreover, transient transfection with constitutively active MEK1, an upstream regulator of ERK, increased Akt phosphorylation and activation, whereas overexpression of constitutively active Akt failed to stimulate ERK phosphorylation. Ouabain at low concentrations also promoted cell proliferation in an ERK-dependent manner. These findings suggest that ouabain-stimulated ERK phosphorylation is required for Akt phosphorylation on Ser(473), cell proliferation, and stimulation of Na(+)/K(+)-ATPase-mediated (86)Rb uptake in OK cells.
机译：内源性强心苷与质膜钠泵（Na（+）/ K（+）-ATPase）的抑制性结合位点结合。内源性强心苷的血浆水平在某些疾病状态下会增加，例如原发性高血压和尿毒症。低浓度的哇巴因不抑制Na（+）/ K（+）-ATPase，诱导细胞增殖。哇巴因介导的反应机制仍不清楚。最近，我们证明在负鼠肾（OK）的近端肾小管细胞中，低浓度的哇巴因通过钙依赖的蛋白激酶B（Akt）的磷酸化诱导细胞增殖。在本研究中，我们确定ERK是在哇巴因刺激的细胞中调节Akt激活的上游激酶。此外，我们提供的证据表明，低浓度的哇巴因以Akt，ERK和Src激酶依赖性方式刺激Na（+）/ K（+）-ATPase介导的（86）Rb吸收。哇巴因介导的ERK磷酸化受到细胞内钙释放，钙进入，酪氨酸激酶和磷脂酶C的抑制。磷酸肌醇3激酶和Akt的药理抑制作用不能抑制哇巴因刺激的ERK磷酸化。哇巴因介导的Akt磷酸化受到MEK / ERK抑制剂U0126的抑制，表明哇巴因介导的Akt磷酸化依赖于ERK。在体外激酶测定中，活性重组ERK磷酸化Ser（473）上的重组Akt。此外，组成性活性MEK1（ERK的上游调节剂）的瞬时转染增加了Akt的磷酸化和激活，而组成性活性的Akt的过表达未能刺激ERK的磷酸化。低浓度的瓦巴因也以ERK依赖性方式促进细胞增殖。这些发现表明，哇巴因刺激的ERK磷酸化对于Ser（473）的Akt磷酸化，细胞增殖以及刺激OK细胞中Na（+）/ K（+）-ATPase介导的（86）Rb吸收是必需的。

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