Stayner Cherie, Iglesias Diana M, Goodyer Paul R, Ellis Lana, Germino Greg, Zhou Jing, Eccles Michael R
Developmental Genetics Laboratory, Department of Pathology, University of Otago, Dunedin, New Zealand.
Hum Mol Genet. 2006 Dec 15;15(24):3520-8. doi: 10.1093/hmg/ddl428. Epub 2006 Nov 2.
Mutations in PKD1 cause dominant polycystic kidney disease (PKD), characterized by large fluid-filled kidney cysts in adult life, but the molecular mechanism of cystogenesis remains obscure. Ostrom et al. [Dev. Biol., 219, 250-258 (2000)] showed that reduced dosage of Pax2 caused increased apoptosis, and ameliorated cystogenesis in Cpk mutant mice with recessive PKD. Pax2 is expressed in condensing metanephrogenic mesenchyme and arborizing ureteric bud, and plays an important role in kidney development. Transient Pax2 expression during fetal kidney mesenchyme-to-epithelial transition, as well as in nascent tubules, is followed by marked down-regulation of Pax2 expression. Here, we show that in humans with PKD, as well as in Pkd1(del34/del34) mutant mice, Pax2 was expressed in cyst epithelial cells, and facilitated cyst growth in Pkd1(del34/del34) mutant mice. In Pkd1(del34/del34) mutant kidneys, the expression of Pax2 persisted in nascent collecting ducts. In contrast, homozygous Pkd1(del34/del34) fetal mice carrying mutant Pax2 exhibited ameliorated cyst growth, although reduced cystogenesis was not associated with increased apoptosis. Pax2 expression was attenuated in nascent collecting ducts and absent from remnant cysts of Pkd1(del34/del34)/Pax2(1Neu/+) mutant mice. To investigate whether the Pkd1 gene product, Polycystin-1, regulates Pax2, MDCK cells were engineered constitutively expressing wild-type Pkd1; Pax2 protein levels and promoter activity were both repressed in MDCK cells over-expressing Pkd1, but not in cells without transgenic Pkd1. These data suggest that polycystin-1-deficient tubular epithelia persistently express Pax2 in ADPKD, and that Pax2 or its pathway may be an appropriate target for the development of novel therapies for ADPKD.
PKD1基因突变会导致显性多囊肾病（PKD），其特征是成年后肾脏出现大量充满液体的囊肿，但囊肿形成的分子机制仍不清楚。奥斯特罗姆等人[《发育生物学》，219卷，250 - 258页（2000年）]表明，Pax2剂量减少会导致凋亡增加，并改善隐性PKD的Cpk突变小鼠的囊肿形成。Pax2在凝聚的后肾间充质和分支的输尿管芽中表达，在肾脏发育中起重要作用。在胎儿肾脏间充质向上皮细胞转变期间以及在新生小管中短暂表达Pax2之后，Pax2表达会显著下调。在此，我们表明，在患有PKD的人类以及Pkd1(del34/del34)突变小鼠中，Pax2在囊肿上皮细胞中表达，并促进Pkd1(del34/del34)突变小鼠的囊肿生长。在Pkd1(del34/del34)突变肾脏中，Pax2的表达在新生集合管中持续存在。相比之下，携带突变型Pax2的纯合Pkd1(del34/del34)胎鼠囊肿生长有所改善，尽管囊肿形成减少与凋亡增加无关。Pax2表达在新生集合管中减弱，并且在Pkd1(del34/del34)/Pax2(1Neu/+)突变小鼠的残余囊肿中不存在。为了研究Pkd1基因产物多囊蛋白-1是否调节Pax2，构建了组成性表达野生型Pkd1的MDCK细胞；在过表达Pkd1的MDCK细胞中，Pax2蛋白水平和启动子活性均受到抑制，但在没有转基因Pkd1的细胞中则没有。这些数据表明，多囊蛋白-1缺陷的肾小管上皮细胞在常染色体显性多囊肾病中持续表达Pax2，并且Pax2或其信号通路可能是开发常染色体显性多囊肾病新疗法的合适靶点。
