Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction
Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction
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DOI：
10.1681/asn.2005080830
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发表时间：
2006-04-01
影响因子：
13.6
通讯作者：
Zhou, Jing
中科院分区：
文献类型：
--
作者：
Nauli, Surya M.;Rossetti, Sandro;Zhou, Jing
“两次击中”假说预测，除了种系突变外，第二次体细胞击中是囊肿发生的先决条件，并已被提出来解释常染色体显性遗传性多囊肾病（ADPKD）中肾囊肿形成的局灶性。先前报道Pkd 1（null/null）小鼠肾上皮细胞对流动刺激无反应。该报告显示，Pkd 1（+/null）细胞能够通过以与野生型细胞类似的方式改变其细胞内钙浓度来响应机械流刺激。本文报道了人肾上皮细胞比小鼠肾上皮细胞需要更高水平的剪切应力来引起细胞内钙离子的增加。来源于正常和非扩张ADPKD人肾小管的永生化和原代培养的肾上皮细胞显示正常的多囊蛋白纤毛表达，并对流体流动剪切力产生反应，细胞溶质钙发生典型变化。相比之下，来自PKD 1突变或多囊蛋白-1或-2纤毛表达异常的ADPKD患者的永生化和原代培养的囊肿衬里上皮细胞对流体剪切力没有反应。这些数据支持两次打击假说作为囊肿形成的机制。本报告提出，钙对流体流动剪切应力的反应可用作多囊蛋白功能的读数，肾小管上皮细胞的机械感觉丧失是PKD囊肿的一个特征。
A "two-hit" hypothesis predicts a second somatic hit, in addition to the germline mutation, as a prerequisite to cystogenesis and has been proposed to explain the focal nature for renal cyst formation in autosomal dominant polycystic kidney disease (ADPKD). It was reported previously that Pkd1(null/null) mouse kidney epithelial cells are unresponsive to flow stimulation. This report shows that Pkd1(+/null) cells are capable of responding to mechanical flow stimulation by changing their intracellular calcium concentration in a manner similar to that of wild-type cells. This paper reports that human renal epithelia require a higher level of shear stress to evoke a cytosolic calcium increase than do mouse renal epithelia. Both immortalized and primary cultured renal epithelial cells that originate from normal and nondilated ADPKD human kidney tubules display normal ciliary expression of the polycystins and respond to fluid-flow shear stress with the typical change in cytosolic calcium. In contrast, immortalized and primary cultured cyst-lining epithelial cells from ADPKD patients with mutations in PKD1 or with abnormal ciliary expression of polycystin-1 or -2 were not responsive to fluid shear stress. These data support a two-hit hypothesis as a mechanism of cystogenesis. This report proposes that calcium response to fluid-flow shear stress can be used as a readout of polycystin function and that loss of mechanosensation in the renal tubular epithelia is a feature of PKD cysts.