最终尿液体积和浓度由通过收集管中的水通道蛋白水通道蛋白(AQP)-2、-3和-4的水重吸收来定义。然而,这些AQPs的转录调控尚不清楚。Hippo/Yes相关蛋白1(YAP)通路在器官大小控制和组织稳态中起重要作用。当包括Mst1/Mst2激酶的Hippo途径被抑制时,YAP被激活并作为转录共激活因子发挥作用。我们之前的工作揭示了肾小管YAP激活在慢性肾病中的病理作用,但YAP在肾脏中的生理作用仍有待确立。这里,我们发现,小管特异性Yap基因敲除小鼠的尿量增加,尿渗透压降低.在Yap敲除小鼠中,肾脏中Aqp2、-3和-4mRNA和蛋白质丰度的降低是明显的。对Mst1/Mst2双敲除和Mst1/Mst2/Yap三敲除小鼠的剖析显示,Aqp2和Aqp4而非Aqp3的表达依附于YAP。此外,将YAP募集到Aqp2和Aqp4基因的启动子并刺激它们的转录。有趣的是,发现YAP与转录因子GATA2,GATA3和NFATc1相互作用。这三种因子以YAP依赖性方式促进Aqp2在收集管细胞中的转录。这三个因子也促进Aqp4转录,而仅GATA2和GATA3增强Aqp3转录。因此,我们的结果表明,YAP促进Aqp2和Aqp4转录,与GATA2,GATA3和NFATc1相互作用以控制Aqp2表达,而Aqp-2、-3和-4利用重叠机制进行基线转录调控。
Final urine volume and concentration are defined by water reabsorption through the water channel proteins aquaporin (AQP)-2, -3 and -4 in the collecting duct. However, the transcriptional regulation of these AQPs is not well understood. The Hippo/Yes-associated protein 1 (YAP) pathway plays an important role in organ size control and tissue homeostasis. When the Hippo pathway including the Mst1/Mst2 kinases is inhibited, YAP is activated and functions as a transcription co-activator. Our previous work revealed a pathological role of tubular YAP activation in chronic kidney disease, but the physiological role of YAP in the kidney remains to be established. Here, we found that tubule-specific Yap knockout mice showed increased urine output and decreased urinary osmolality. Decreases in
Aqp2, -3 and -4 mRNA and protein abundance in the kidney were evident in Yap knockout mice. Analysis of Mst1/Mst2 double knockout and Mst1/Mst2/Yap triple knockout mice showed that expression of
Aqp2 and Aqp4 but not Aqp3 was dependent on YAP. Furthermore, YAP was recruited to the promoters of the Aqp2 and Aqp4 genes and stimulated their transcription. Interestingly, YAP was found to interact with transcription factors GATA2, GATA3 and NFATc1. These three factors promoted
Aqp2 transcription in a YAP dependent manner in collecting duct cells. These three factors also promoted Aqp4 transcription whereas only GATA2 and GATA3 enhanced Aqp3 transcription. Thus, our results suggest that YAP promotes
Aqp2 and Aqp4 transcription, interacts with GATA2, GATA3 and NFATc1 to control
Aqp2 expression, while Aqp-2, -3 and -4 exploit overlapping mechanisms for their baseline transcriptional regulation.