Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.
Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.
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DOI：
10.1172/jci22850
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发表时间：
2005-04
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影响因子：
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通讯作者：
Saori Nishio;M. Hatano;Michio Nagata;S. Horie;T. Koike;T. Tokuhisa;T. Mochizuki
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文献类型：
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作者：
Saori Nishio;M. Hatano;Michio Nagata;S. Horie;T. Koike;T. Tokuhisa;T. Mochizuki
常染色体显性遗传性多囊肾病（ADPKD）是人类最常见的单基因遗传病，其特征是进行性双侧肾囊肿和肾功能不全的发展。ADPKD的囊肿形成被认为是PKD缺陷（PKD（-/-））肾小管上皮细胞的单克隆增殖。为了确定Pkd 1的功能，我们通过聚集来自ROSA 26小鼠的Pkd 1（-/-）ES细胞和Pkd 1（+/+）桑椹胚来产生嵌合小鼠。与ADPKD患者一样，这些小鼠在肾脏、肝脏和胰腺中出现囊肿。令人惊讶的是，在囊肿形成的早期阶段，肾脏的囊肿上皮由Pkd 1（-/-）和Pkd 1（+/+）肾小管上皮细胞组成。Pkd 1（-/-）囊肿上皮细胞由立方形变为扁平形，并在中期取代JNK介导凋亡丢失的Pkd 1（+/+）囊肿上皮细胞。在晚期囊肿中，Pkd 1（-/-）细胞继续永生化增殖，下调p53。这些结果为ADPKD患者的囊肿形成提供了新的认识。此外，在来自Pkd 1（-/-）小鼠的小鼠胚胎成纤维细胞的3 T3型培养物中经常观察到不诱导p53的永生化增殖。因此，Pkd 1通过诱导p53和激活JNK在防止肾小管上皮细胞的永生化增殖中起作用。
Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed 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(+/+) morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1(-/-) and Pkd1(+/+) renal tubular epithelial cells in the early stages of cystogenesis. Pkd1(-/-) cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1(+/+) cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1(-/-) cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of 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 the induction of p53 and activation of JNK.