Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy
Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy
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Yes相关蛋白调节阿霉素肾病足细胞细胞周期重入和去分化
DOI：
10.1038/s41419-019-2139-3
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发表时间：
2019-12-04
影响因子：
9
通讯作者：
Gu, Leyi
中科院分区：
文献类型：
--
作者：
Xie, Kewei;Xu, Chenqi;Gu, Leyi
足细胞是终末分化的细胞，几乎没有增殖能力。细胞周期抑制蛋白p21、p27、p57的高表达在维持成熟足细胞低水平增殖中发挥重要作用。在本研究中，我们旨在探讨yes相关蛋白（YAP）信号在阿霉素诱导的足细胞重新进入细胞周期和去分化中的作用。在阿霉素肾病小鼠中发现增殖细胞核抗原(PCNA)-、细胞周期蛋白依赖性激酶4 (CDK4)-和细胞周期蛋白d1阳性足细胞。在体外，阿霉素增加了S期细胞的百分比，上调了间充质相关标记蛋白的表达。CDK4和cyclin D1与阿霉素孵育后显著上调。足细胞中YAP的过表达促进其进入细胞周期；上调cyclin D1、desmin和snail2的表达，下调Wilms ' tumor 1 （WT1）和nephrin的产生。重组小鼠fgf -碱性诱导足细胞重新进入细胞周期，抑制WT1和nephrin，增加desmin和snail2的表达。用YAP/ TEA结构域转录因子（TEAD）抑制剂verteporfin预处理足细胞，可降低阿霉素诱导的cyclin D1过表达，减少s期足细胞的比例。通过RNA干扰敲低yapp的表达进一步验证了这一结果。综上所述，阿霉素通过上调CDK4和cyclin D1表达诱导足细胞重新进入细胞周期，这至少部分是由YAP信号传导介导的。重新进入细胞周期诱导足细胞间充质标记物的过度表达。
Podocytes are terminally differentiated cells with little proliferative capacity. The high expression levels of cell cycle inhibitory proteins, including p21, p27, and p57, play an important role in maintaining the low level of proliferation of mature podocytes. In the present study, we aimed to explore the role of yes-associated protein (YAP) signalling in adriamycin-induced podocyte re-entry into the cell cycle and dedifferentiation. Proliferating cell nuclear antigen (PCNA)-, cyclin-dependent kinase 4 (CDK4)-, and Cyclin D1-positive podocytes were found in mice with adriamycin-induced nephropathy. In vitro, adriamycin administration increased the percentage of cells in S phase and the upregulation of mesenchymal-related marker proteins. CDK4 and cyclin D1 were significantly up-regulated after incubation with adriamycin. Overexpression of YAP in podocytes promoted their entry into the cell cycle; up-regulated cyclin D1, desmin, and snail2 expression and down-regulated Wilms’ tumour 1 (WT1) and nephrin production. Recombinant murine FGF-basic induced podocytes to re-enter the cell cycle, inhibited WT1 and nephrin, and increased desmin and snail2 expression. Pretreating podocytes with verteporfin, an inhibitor of YAP/ TEA domain transcription factor (TEAD), decreased the adriamycin-induced overexpression of cyclin D1 and reduced the ratio of S-phase podocytes. This result was further verified by knocking downYAPexpression using RNA interference. In conclusion, adriamycin induced podocytes to re-enter the cell cycle via upregulation of CDK4 and cyclin D1 expression, which was at least partly mediated by YAP signalling. Re-entry into the cell cycle induced the over-expression of mesenchymal markers in podocytes.