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Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells

机译:氟伐他汀通过人肾小球系膜细胞中甲羟戊酸的消耗来减弱IGF-1诱导的ERK1 / 2活化和细胞增殖

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Aims: Insulin-like growth factor (IGF)-1 is a major mitogenic growth factor for mesangial cells (MCs). Statins slow the progression of chronic kidney disease by affecting inflammatory cell signaling pathways, in addition to improving lipid profile, however, no studies have investigated the effects of fluvastatin on mitogen- activated protein (MAP) kinase activity or MC proliferation in kidney cells. We investigated the effects of fluvastatin on IGF-1-induced activation of intracellular signal pathways and MC proliferation, and examined the inhibitory mechanisms of fluvastatin.Main methods: Western blotting and cell proliferation assay were used.Key findings: IGF-1 induced phosphorylation of extracellular-related kinase (ERK)1/2, MAP or ERK kinase (MEK)1/2, and Akt, expression of cydin D1, and MC proliferation in cultured human MCs. Fluvastatin or PD98059, an MEK1 inhibitor, completely abolished IGF-1-induced MEK1/2 and ERK1/2 phosphorylation and MC proliferation, whereas inhibition of Akt had no effect on MC proliferation. Mevalonic acid prevented fluvastatin inhibition of IGF-1-induced MEK1/2 and ERK1/2 phosphorylation, cyclin Dl expression, and MC proliferation.Significance: Fluvastatin inhibits IGF-1-induced activation of the MAP kinase pathway and MC proliferation by mevalonic acid depletion, and might have renoprotective effects by inhibiting IGF-1-mediated MC proliferation.
机译:目的:胰岛素样生长因子(IGF)-1是肾小球膜细胞(MCs)的主要促有丝分裂生长因子。他汀类药物除了改善脂质分布外,还通过影响炎性细胞信号传导通路来延缓慢性肾脏病的进展,但是,尚无研究研究氟伐他汀对肾细胞中促分裂原活化蛋白(MAP)激酶活性或MC增殖的影响。我们研究了氟伐他汀对IGF-1诱导的细胞内信号通路激活和MC增殖的影响,并研究了氟伐他汀的抑制机制。主要方法:采用Western印迹和细胞增殖测定。主要发现:IGF-1诱导的磷酸化细胞外相关激酶(ERK)1/2,MAP或ERK激酶(MEK)1/2和Akt,cydin D1的表达以及培养的人MC中MC的增殖。氟伐他汀或MEK1抑制剂PD98059完全消除了IGF-1诱导的MEK1 / 2和ERK1 / 2磷酸化以及MC增殖,而抑制Akt对MC增殖没有影响。甲羟戊酸可预防氟伐他汀抑制IGF-1诱导的MEK1 / 2和ERK1 / 2磷酸化,cyclin D1表达和MC增殖。意义:氟伐他汀可抑制IGF-1诱导的甲羟戊酸耗尽对MAP激酶途径的激活和MC增殖。 ,并且可能通过抑制IGF-1介导的MC增殖而具有肾脏保护作用。

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