YAP-mediated mechanotransduction determines the podocyte's response to damage
YAP-mediated mechanotransduction determines the podocyte's response to damage
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DOI：
10.1126/scisignal.aaf8165
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发表时间：
2017-04-11
影响因子：
7.3
通讯作者：
Schermer, Bernhard
中科院分区：
文献类型：
--
作者：
Rinschen, Markus M.;Grahammer, Florian;Schermer, Bernhard
足细胞是肾脏过滤屏障的终末分化细胞。它们承受生理过滤压力和相当大的机械应变，在各种肾脏疾病中，机械应变可能进一步增加。当损伤导致细胞骨架重组和这些细胞的形态改变时，过滤屏障可能会受到损害，并使蛋白质渗漏到尿液中（这种情况称为蛋白尿）。使用时间分辨蛋白质组学，我们发现足细胞损伤在蛋白尿发生之前刺激肾小球疾病大鼠模型中转录共激活因子 YAP 的活性和 YAP 靶基因的表达。尽管在大多数细胞类型中，YAP 及其直系同源物 TAZ 的活性是由机械应力激活的，但损伤会降低在坚硬基质上生长的培养的人类和小鼠足细胞系中的 YAP 和 TAZ 活性。在软基质上培养这些细胞或抑制应力纤维形成重现了体内观察到的损伤诱导的 YAP 上调，表明足细胞中 YAP 激活的机械转导依赖性机制。 YAP 在培养的足细胞中过度表达会增加细胞外基质相关蛋白的丰度，从而导致纤维化。在糖尿病肾病小鼠模型中，YAP 活性增加，并且 YAP 目标 CTGF 在肾小球疾病患者的肾活检中高表达。尽管人 YAP 在小鼠中的过度表达会引起轻度蛋白尿，但在大鼠中对 YAP 与其伙伴 TEAD 之间的相互作用进行药理抑制可改善肾小球疾病并减少肾小球中损伤诱导的机械信号传导。因此，YAP 依赖性机械信号传导的扰动是治疗某些肾小球疾病的潜在治疗靶点。
Podocytes are terminally differentiated cells of the kidney filtration barrier. They are subjected to physiological filtration pressure and considerable mechanical strain, which can be further increased in various kidney diseases. When injury causes cytoskeletal reorganization and morphological alterations of these cells, the filtration barrier may become compromised and allow proteins to leak into the urine (a condition called proteinuria). Using time-resolved proteomics, we showed that podocyte injury stimulated the activity of the transcriptional coactivator YAP and the expression of YAP target genes in a rat model of glomerular disease before the development of proteinuria. Although the activities of YAP and its ortholog TAZ are activated by mechanical stress in most cell types, injury reduced YAP and TAZ activity in cultured human and mouse podocyte cell lines grown on stiff substrates. Culturing these cells on soft matrix or inhibiting stress fiber formation recapitulated the damage-induced YAP up-regulation observed in vivo, indicating a mechanotransduction-dependent mechanism of YAP activation in podocytes. YAP overexpression in cultured podocytes increased the abundance of extracellular matrix-related proteins that can contribute to fibrosis. YAP activity was increased in mouse models of diabetic nephropathy, and the YAP target CTGF was highly expressed in renal biopsies from glomerular disease patients. Although overexpression of human YAP in mice induced mild proteinuria, pharmacological inhibition of the interaction between YAP and its partner TEAD in rats ameliorated glomerular disease and reduced damage-induced mechanosignaling in the glomeruli. Thus, perturbation of YAP-dependent mechanosignaling is a potential therapeutic target for treating some glomerular diseases.