Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Am Soc Nephrol. 2010 Sep;21(9):1521-32. doi: 10.1681/ASN.2010010127. Epub 2010 Aug 12.
Mutations in PKD1, which encodes polycystin-1 (PC1), contribute to >85% of cases of autosomal dominant polycystic kidney disease (ADPKD). The planar cell polarity (PCP) pathway is necessary for the oriented cell division and convergent extension that establishes and maintains the structure of kidney tubules, but the role of this pathway in the pathophysiology of ADPKD is incompletely understood. Here, we show that inactivation of Pkd1 in postnatal developing mouse kidneys leads to a defect in oriented cell division in precystic kidney tubules. We also observed this defect in precystic Pkd1-inactivated mature kidneys subjected to ischemia-reperfusion injury as a "third hit." Cystic kidneys exhibited striking upregulation and activation of Frizzled 3 (Fz3), a regulator of PCP, and its downstream effector, CDC42. Precystic kidneys demonstrated upregulation of CDC42, but the localization of the polarity proteins Par3 and Par6 was similar to control. Fz3 was expressed on the cilia of cystic kidneys but barely detected on the cilia of normal kidneys. In vitro, PC1 and Fz3 antagonized each other to control CDC42 expression and the rate of cell migration in HEK293T cells. Taken together, our data suggest that PC1 controls oriented cell division and that aberrant PCP signaling contributes to cystogenesis.
PKD1 基因突变导致常染色体显性多囊肾病（ADPKD）的 85%以上病例。平面细胞极性（PCP）途径对于定向细胞分裂和汇聚延伸是必需的，这些过程建立并维持了肾小管的结构，但该途径在 ADPKD 病理生理学中的作用尚未完全阐明。在这里，我们表明，在出生后发育中的小鼠肾脏中敲除 Pkd1 会导致未囊化的肾小管中定向细胞分裂的缺陷。我们还观察到，在缺血再灌注损伤的 Pkd1 失活的成熟肾脏中也存在这种缺陷，这是“第三次打击”。囊性肾脏中Frizzled 3（Fz3）的上调和激活显著上调，Fz3 是 PCP 的调节剂及其下游效应物 CDC42。未囊化的肾脏中 CDC42 的表达上调，但极性蛋白 Par3 和 Par6 的定位与对照相似。Fz3 在囊性肾脏的纤毛上表达，但在正常肾脏的纤毛上几乎检测不到。在体外，PC1 和 Fz3 相互拮抗，控制 HEK293T 细胞中 CDC42 的表达和细胞迁移率。总之，我们的数据表明 PC1 控制定向细胞分裂，异常的 PCP 信号转导导致囊肿形成。
