The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Development. 2010 Apr;137(7):1075-84. doi: 10.1242/dev.049437. Epub 2010 Feb 24.
Polycystin 1 and polycystin 2 are large transmembrane proteins, which, when mutated, cause autosomal dominant polycystic kidney disease (ADPKD), a highly prevalent human genetic disease. The polycystins are thought to form a receptor-calcium channel complex in the plasma membrane of renal epithelial cells and elicit a calcium influx in response to mechanical stimulation, such as fluid flow across the apical surface of renal epithelial cells. The functional role of the polycystins in mechanosensation remains largely unknown. Here, we found that myocyte enhancer factor 2C (MEF2C) and histone deacetylase 5 (HDAC5), two key regulators of cardiac hypertrophy, are targets of polycystin-dependent fluid stress sensing in renal epithelial cells in mice. We show that fluid flow stimulation of polarized epithelial monolayers induced phosphorylation and nuclear export of HDAC5, which are crucial events in the activation of MEF2C-based transcription. Kidney-specific knockout of Mef2c, or genetrap-inactivation of a MEF2C transcriptional target, MIM, resulted in extensive renal tubule dilation and cysts, whereas Hdac5 heterozygosity or treatment with TSA, an HDAC inhibitor, reduced cyst formation in Pkd2(-/-) mouse embryos. These findings suggest a common signaling motif between myocardial hypertrophy and maintenance of renal epithelial architecture, and a potential therapeutic approach to treat ADPKD.
多囊蛋白 1 和多囊蛋白 2 是两种大型跨膜蛋白，当它们发生突变时，会导致常染色体显性多囊肾病（ADPKD），这是一种常见的人类遗传性疾病。多囊蛋白被认为在肾上皮细胞的质膜中形成受体-钙通道复合物，并在机械刺激（如肾上皮细胞顶表面的流体流动）下引发钙内流。多囊蛋白在机械感觉中的功能作用在很大程度上仍然未知。在这里，我们发现肌细胞增强因子 2C（MEF2C）和组蛋白去乙酰化酶 5（HDAC5），这两种心脏肥大的关键调节剂，是肾上皮细胞中多囊蛋白依赖的流体应激感应的靶点。我们表明，极化上皮单层的流体流动刺激诱导了 HDAC5 的磷酸化和核输出，这是 MEF2C 为基础的转录激活的关键事件。肾特异性敲除 Mef2c，或 MEF2C 转录靶标 MIM 的基因捕获失活，导致广泛的肾小管扩张和囊肿，而 HDAC5 杂合性或用 TSA（一种 HDAC 抑制剂）治疗，可减少 Pkd2(-/-) 小鼠胚胎中的囊肿形成。这些发现表明心肌肥大和维持肾上皮结构之间存在共同的信号基序，为治疗 ADPKD 提供了一种潜在的治疗方法。
