Cystogenesis in the gene targeting mice of autosomal dominant polycystic kidney disease (ADPKD)

常染色体显性多囊肾病（ADPKD）是一种最常见的人类单基因遗传病，以进行性双侧肾囊肿和肾功能不全为特征。ADPKD的囊成被认为是PKD缺陷（PKD^<-/->）肾小管上皮细胞的单克隆增殖。为了确定Pkd1的功能，我们将ROSA26小鼠的Pkd1^<-/-> ES细胞和Pkd1^<+/+>森葚胚聚集在一起，生成嵌合小鼠。与人类ADPKD一样，这些小鼠的肾脏、肝脏和胰腺也出现了囊肿。令人惊讶的是，肾脏的囊肿上皮在膀胱形成的早期阶段由Pkd1^<-/->和Pkd1^<+/+>肾小管上皮细胞组成。Pkd1^<-/->囊肿上皮细胞由立方体变为扁平，取代了jnk介导的中期凋亡丢失的Pkd1^<+/+>囊肿上皮细胞。在晚期囊肿中，Pkd1^<-/->细胞在p53下调的情况下继续永生化增殖。这些结果为ADPKD患者的膀胱发生提供了一个新的场景。此外，在Pkd1^<-/->小鼠胚胎成纤维细胞的3T3型培养中，经常观察到不诱导p53的永生化增殖。因此，Pkd1通过诱导p53和激活JNK，在阻止肾小管上皮细胞永生化增殖中发挥作用。

Autosomal dominant polycystic kidney disease (ADPKD) is a most common human monogenic genetic disorder characterized by progressive bilateral renal cysts and develops renal insufficiency. Cystogenesis of ADPKD is considered to be a monoclonal proliferation of PKD-deficient (PKD^<-/->) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1^<-/-> ES cells and Pkd1^<+/+> morula from ROSA26 mice. Like human ADPKD, these mice developed cysts in kidney, liver and pancreas. Surprisingly, cyst epithelium in the kidney was composed of both Pkd1^<-/-> and Pkd1^<+/+> renal tubular epithelial cells at early stages of cystogenesis. Pkd1^<-/-> cyst epithelial cells changed shape from cuboidal to flat and replaced Pkd1^<+/+> cyst epithelial cells lost by JNK-mediated apoptosis at intermediate stages. In late stage cysts, Pkd1^<-/-> cells continued immortalized proliferation with down-regulation of p53. These results provide a novel scenario in the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3 type culture of mouse embryonic fibroblasts from Pkd1^<-/-> mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through induction of p53 and activation of JNK.