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首页> 外文期刊>American Journal of Physiology >Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation.
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Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation.

机译：醛固酮诱导的系膜细胞增殖由EGF受体反式激活介导。

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Aldosterone (Aldo) stimulates glomerular mesangial cell (MC) proliferation, in part, through an ERK1/2-dependent pathway. In this study, we examined whether Aldo activation of ERK1/2 in MC is mediated through redox-dependent EGF receptor (EGFR) transactivation, as well as the involvement of other signaling mechanisms in Aldo-induced MC proliferation. Aldo increased human MC proliferation, as determined by [(3)H]thymidine incorporation and cell counts. This increase in proliferation was blocked by inhibition of the mineralocorticoid receptor (MR). Continuing our observations downstream in the signaling pathway, we examined the ability of Aldo to activate both the Ras/MAPK and the PI3K signaling pathways. Aldo increased Ki-RasA and Ki-RasA:GTP levels, and sequentially phosphorylated c-Raf, MAPK kinase (MEK1/2), and ERK1/2. Ki-RasA small interfering RNA (siRNA), the c-Raf inhibitor GW5074, and the MEK1/2 inhibitor PD98059 reduced Aldo-induced cell proliferation by approximately 65%. Aldo also increased phosphorylation of PI3K, Akt, the mammalian target of rapamycin (mTOR), and the 70-kDa ribosomal S6 kinase (p70S6K1). Inhibition of the PI3K pathways by the selective PI3K inhibitor LY 294002, an Akt inhibitor, or the mTOR inhibitor rapamycin reduced cell proliferation by 51%. Combining LY 294002 and PD98059 completely blocked Aldo-induced MC proliferation. Next, we confirmed that Aldo exerts its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the EGFR. Pretreatment with the EGFR antagonist AG1478 inhibited MC proliferation, as well as the activation of Ras/MAPK and PI3K/Akt, suggesting that Ras/MAPK and PI3K/Akt activation occur downstream of EGFR activation. Finally, we examined the role of reactive oxygen species (ROS) in Aldo-induced transactivation of the EGFR. Aldo-induced ROS were predominantly generated by mitochondria. Pretreatment with the antioxidant N-acetyl-l-cysteine, catalase, SOD, mitochondrial respiratory chain complex I inhibitor rotenone (Rot), NADPH oxidase inhibitor apocynin, and DPI significantly inhibited Aldo-stimulated MC proliferation as well as EGFR transactivation. However, Rot reduced MC proliferation more potently than apocynin and DPI. In conclusion, Aldo stimulated cell proliferation through MR-mediated, redox-sensitive EGFR transactivation, which was dependent on the Ki-RasA/c-Raf/MEK/ERK and PI3K/Akt/mTOR/p70S6K1 signaling pathways in human MCs.
机译：醛固酮（Aldo）部分通过ERK1 / 2依赖性途径刺激肾小球系膜细胞（MC）增殖。在这项研究中，我们检查了Aldo在MC中ERK1 / 2的激活是否通过氧化还原依赖性EGF受体（EGFR）反式激活介导，以及其他信号机制是否参与Aldo诱导的MC增殖。通过[（3）H]胸苷掺入和细胞计数确定，Aldo增加了人MC的增殖。抑制盐皮质激素受体（MR）阻止了增殖的增加。继续我们在信号通路下游的观察，我们研究了Aldo激活Ras / MAPK和PI3K信号通路的能力。 Aldo增加Ki-RasA和Ki-RasA：GTP水平，并依次磷酸化c-Raf，MAPK激酶（MEK1 / 2）和ERK1 / 2。 Ki-RasA小干扰RNA（siRNA），c-Raf抑制剂GW5074和MEK1 / 2抑制剂PD98059将Aldo诱导的细胞增殖降低了约65％。 Aldo还增加了PI3K，Akt，雷帕霉素（mTOR）的哺乳动物靶标和70 kDa核糖体S6激酶（p70S6K1）的磷酸化。选择性PI3K抑制剂LY 294002，Akt抑制剂或mTOR抑制剂雷帕霉素对PI3K途径的抑制作用使细胞增殖减少了51％。 LY 294002和PD98059的结合完全阻断了Aldo诱导的MC增殖。接下来，我们确认Aldo通过激活EGFR对MAPK和PI3K激活以及细胞增殖发挥作用。 EGFR拮抗剂AG1478的预处理抑制MC增殖以及Ras / MAPK和PI3K / Akt的激活，这表明Ras / MAPK和PI3K / Akt激活发生在EGFR激活的下游。最后，我们研究了活性氧（ROS）在Aldo诱导的EGFR反式激活中的作用。 Aldo诱导的ROS主要由线粒体产生。用抗氧化剂N-乙酰基-1-半胱氨酸，过氧化氢酶，SOD，线粒体呼吸链复合体I抑制剂鱼藤酮（Rot），NADPH氧化酶抑制剂Apocynin和DPI进行预处理可显着抑制Aldo刺激的MC增殖以及EGFR反式激活。然而，腐烂剂比载脂蛋白和DPI更有效地降低MC增殖。总之，Aldo通过MR介导的氧化还原敏感性EGFR反式激活刺激细胞增殖，这依赖于人类MC中的Ki-RasA / c-Raf / MEK / ERK和PI3K / Akt / mTOR / p70S6K1信号通路。

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