Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
J Pathol. 2011 May;224(1):133-42. doi: 10.1002/path.2856. Epub 2011 Mar 7.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive deterioration of renal function and formation of cysts, and is an important cause of end-stage renal disease. Previously we showed that tubular epithelial injury accelerates cyst formation in inducible Pkd1-deletion mice. In these mice, expression of the planar cell polarity (PCP) component Four-jointed (Fjx1) is decreased during epithelial repair, while in control mice Fjx1 expression is increased and may be required during tissue regeneration. In cystic kidneys, however, Fjx1 expression is also increased. Besides a PCP component, Four-jointed is also implicated in the Hippo-signalling pathway. This pathway is involved in organ size control by regulating proliferation and apoptosis. The role of Hippo signalling, together with the opposing expression pattern of Fjx1 during epithelial repair and at cystic stages, triggered us to investigate the activity of the Hippo pathway during these processes. Therefore, we examined its final effector molecule, the transcriptional co-activator Yes-associated protein (YAP) and observed that during tissue repair, YAP expression was not different between Pkd1-deletion mice and controls, ie during tissue regeneration YAP expression was increased and predominantly localized in the cytoplasm but normalized after tissue repair. At a later stage, however, in cystic epithelia and epithelia of dilated tubules, strong nuclear YAP accumulation was observed, accompanied by up-regulation of the YAP transcriptional targets Birc-3, Ctgf, InhbA, and Fjx1. Altered activity of the Hippo pathway was confirmed in renal tissues from human ADPKD and ARPKD patients, as well as in cystic renal tumours. Our data strengthen the concept that during epithelial repair Four-jointed is involved in PCP signalling, while in cystic kidneys it is related to Hippo signalling and cyst growth.
常染色体显性多囊肾病 (ADPKD) 的特征是肾功能进行性恶化和囊肿形成，是终末期肾病的重要原因。此前我们表明，诱导性 Pkd1 缺失小鼠中管状上皮损伤会加速囊肿形成。在这些小鼠中，上皮修复过程中平面细胞极性 (PCP) 成分 Four-jointed (Fjx1) 的表达减少，而在对照小鼠中 Fjx1 的表达增加，可能在组织再生过程中需要。然而，在囊性肾脏中，Fjx1 的表达也增加了。除了作为 PCP 成分外，Four-jointed 还与 Hippo 信号通路有关。该途径通过调节增殖和凋亡参与器官大小控制。Hippo 信号通路的作用，以及 Fjx1 在上皮修复和囊性阶段的相反表达模式，促使我们研究该通路在这些过程中的活性。因此，我们检查了其最终效应分子转录共激活因子 Yes 相关蛋白 (YAP)，并观察到在组织修复过程中，Pkd1 缺失小鼠和对照组之间 YAP 的表达没有差异，即在组织再生过程中 YAP 的表达增加，主要定位于细胞质中，但在组织修复后恢复正常。然而，在后来的阶段，在囊性上皮和扩张的肾小管上皮中，观察到强烈的核 YAP 积累，伴随着 YAP 转录靶标 Birc-3、Ctgf、InhbA 和 Fjx1 的上调。人 ADPKD 和 ARPKD 患者以及囊性肾肿瘤的肾组织中证实了 Hippo 通路活性的改变。我们的数据强化了这样一种概念，即在上皮修复过程中，Four-jointed 参与 PCP 信号转导，而在囊性肾脏中，它与 Hippo 信号转导和囊肿生长有关。
