Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway.
Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway.
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Cdc42缺陷通过抑制Nwasp/应激纤维/YAP通路诱导足细胞凋亡
DOI：
10.1038/cddis.2016.51
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发表时间：
2016-03-17
影响因子：
9
通讯作者：
Shi W
中科院分区：
文献类型：
--
作者：
Huang Z;Zhang L;Chen Y;Zhang H;Zhang Q;Li R;Ma J;Li Z;Yu C;Lai Y;Lin T;Zhao X;Zhang B;Ye Z;Liu S;Wang W;Liang X;Liao R;Shi W
足细胞凋亡是导致许多慢性肾脏疾病蛋白尿的主要机制。然而，在这些肾脏疾病中引起足细胞凋亡的确切机制尚不完全清楚。Rho家族的小GTP酶已被证明是维持足细胞结构和功能所必需的。最近的研究表明，足细胞特异性缺失Cdc 42在体内，而不是RhoA或Rac 1，导致先天性肾病综合征和肾小球硬化症。然而，由Cdc 42控制的足细胞中的潜在细胞事件仍不清楚。在这里，我们评估了Cdc 42调节足细胞凋亡的细胞机制。我们发现高糖、脂多糖或阿霉素损伤足细胞后Cdc 42的表达及其活性显著降低。小干扰RNA和选择性Cdc 42抑制剂ML-141分别在体外和体内降低Cdc 42表达，导致足细胞凋亡和蛋白尿。我们的研究结果进一步证明，Cdc 42或其下游效应物Nwasp不足可降低足细胞中被认为是抗凋亡蛋白的雅普的mRNA和蛋白表达。此外，我们的数据表明，由Cdc 42/NWasp缺陷引起的应力纤维的损失也降低了Yes相关蛋白（雅普）mRNA和蛋白的表达，并诱导足细胞凋亡。过表达活性雅普可显著抑制Cdc 42/Nwasp/应激纤维缺乏诱导的足细胞凋亡。因此，Cdc 42/Nwasp/应力纤维/雅普信号通路可能在足细胞凋亡调控中发挥重要作用。维持必要的Cdc 42将是预防蛋白尿肾病的一种有效方法。
Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide-or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases.