Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells
Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells
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DOI：
10.1038/ng1076
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发表时间：
2003-02-01
期刊：
影响因子：
30.8
通讯作者：
Zhou, J
中科院分区：
文献类型：
--
作者：
Nauli, SM;Alenghat, FJ;Zhou, J
与多囊肾病 (PKD) 发病机制有关的几种蛋白质定位于纤毛。此外，患有 TgN737Rpw（编码北极星）突变的 PKD 小鼠的纤毛畸形。然而，尚不清楚纤毛功能障碍是否发生或与 PKD 中囊肿的形成有关。在这里，我们发现多囊蛋白-1 (PC1) 和多囊蛋白-2 (PC2) 分别由 Pkd1 和 Pkd2 编码的蛋白质，Pkd1 和 Pkd2 是人常染色体显性 PKD 突变基因的小鼠直系同源物，共同分布在肾上皮的初级纤毛中。从缺乏功能性 PC1 的转基因小鼠中分离出的细胞形成纤毛，但不会响应生理液体流动而增加 Ca2+ 流入。针对 PC2 的阻断抗体与兰尼碱受体的抑制剂类似地消除了野生型细胞中的流动响应，而 G 蛋白、磷脂酶 C 和 InsP(3) 受体的抑制剂则没有效果。这些数据表明，PC1 和 PC2 有助于肾上皮初级纤毛的液体流动感觉，并且它们都在相同的机械传导途径中发挥作用。因此，由于细胞无法感知正常调节组织形态发生的机械信号，PC1 或 PC2 的丢失或功能障碍可能导致 PKD。
Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca2+ influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wildtype cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.