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

常染色体显性多囊肾病 (ADPKD) 基因靶向小鼠的囊肿发生

• 批准号: 15590838
• 负责人: MOCHIZUKI Toshio
• 金额: $ 2.24万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590838/
• 关键词: Polycystic kidney; ADPKD; PKD1; knockout mouse; knockout chimera mouse

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.

常染色体显性遗传性多囊肾病(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为特征，发展为肾功能不全。ADPKD的发生被认为是PKD缺陷型(PKD)肾小管上皮细胞的克隆性增殖。为了确定PKD 1的功能，我们通过聚合PKD 1^&lt；-/-&gt；ES细胞和来自rosa26小鼠的PKD 1^&lt；+/+&gt；桑椹胚来构建嵌合小鼠。与人类ADPKD一样，这些小鼠在肾脏、肝脏和胰腺出现了囊肿。令人惊讶的是，在囊变的早期，肾脏的囊性上皮由PKD1^-lt；-/-&gt；和PKD1^-lt；+/+&gt；肾小管上皮细胞组成。在中期，PKD1^-lt；-/-&gt；囊上皮细胞由立方变为扁平，取代了JNK介导的细胞凋亡所失去的PKD1^&lt；+/+&gt；囊上皮细胞。在晚期囊性病变中，PKD1^&lt；-/-&gt；细胞继续永生增殖并下调P53的表达。这些结果为ADPKD患者的囊变提供了一种新的设想。此外，在3T3型培养的小鼠胚胎成纤维细胞中，经常观察到在没有P53诱导的情况下永生化增殖。因此，PKD1通过诱导P53和JNK的激活，在阻止肾小管上皮细胞永生化增殖中发挥作用。

项目成果

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.

• DOI: 10.1172/jci22850
• 发表时间: 2005-04
• 期刊: The Journal of clinical investigation
• 作者: Saori Nishio;M. Hatano;Michio Nagata;S. Horie;T. Koike;T. Tokuhisa;T. Mochizuki

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

• DOI: 10.1172/jci200522850
• 发表时间: 2005-04-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Nishio, S;Hatano, M;Mochizuki, T
• 通讯作者: Mochizuki, T