Inhibition of 4E-BP1 phosphorylation promotes tubular cell escaping from G2/M arrest and ameliorates kidney fibrosis.
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肾损伤发生时,阻滞于 G2/m 期的肾小管细胞 可能通过产生大量促纤维化的细胞因子而促进间质成纤维细胞活化和肾脏纤维化。 MTORC1信号通路对于控制细胞生长至关重要,然而,MTORC1在肾纤维化过程中调节肾小管细胞周期进程的作用和机制尚不清楚。 本文报道 p-S6丰度在血清刺激后15min 增加,1h 达高峰,3h 至24h 下降, 而 p-4E-BP1和 p-Histone H3丰度在相似模式下从15min 增加到24h。 通过转染具有4个磷酸位点突变(4E-BP1A4)的4E-BP1质粒,可抑制 NRK-52E 细胞中4E-BP1的磷酸化。 4E-BP1A4基因转染减少了 NRK-52E 细胞 G2/m 期阻滞,降低了细胞内促纤维化因子和细胞外间质的产生。 此外,在4E-BP1A4转染的 NRK-52E 细胞中,马兜铃酸诱导的肾小管上皮细胞 G2/m 期阻滞也大大减弱。在 UUO 肾病小鼠肾脏中,有丝分裂小管细胞中 p-4E-BP1丰度明显升高。 因此,这些数据表明,抑制4E-BP1磷酸化可能抑制肾小管细胞 G2/m 期阻滞和肾脏纤维化。 Upon occurrence of kidney injury, tubular cells arrested in G2/M stage may promote interstitial fibroblast activation and kidney fibrosis through producing large amounts of pro-fibrotic cytokines. MTORC1 signaling is essential for controlling cell growth, however, the role and mechanisms for mTORC1 in regulating tubular cell cycle progression during kidney fibrosis are not clear. Here we reported that p-S6 abundance was increased at 15 min, reached peak at 1 h and declined from 3 h to 24 h, while the abundance of p-4E-BP1 and p-Histone H3 was increased from 15 min to 24 h in tubular epithelial cells at the similar pattern after serum stimulation. The phosphorylation of 4E-BP1 was prohibited in NRK-52E cells by the transfection of 4E-BP1 plasmid with four phospho-sites mutation (4E-BP1A4). 4E-BP1A4 transfection led to less G2/M cell arrest as well as the production of pro-fibrotic cytokine and extracellular matrix in NRK-52E cells. In addition, aristolochic acid (AA)-induced tubular cell G2/M arrest induced by treatment was also largely attenuated in NRK-52E cells transfected with 4E-BP1A4. In mouse kidneys with UUO nephropathy, p-4E-BP1 abundance was markedly elevated in the mitotic tubular cells. Therefore, these data indicates that suppressing 4E-BP1 phosphorylation may inhibit tubular cell G2/M-arrest and kidney fibrosis.
Here, we found that 4E-BP1, rather than p-S6, downstream of mTORC1 signaling
regulates cell proliferation in NRK-52E cells. Decreased phosphorylation of 4E-BP1
contributes to epithelial escaping from G2/M arrest, and thereby causing decreased
pro-fibrotic cytokines production.
参考文献:V10.1016/j.cellsig.2019.05.016
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