CIC-5Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease
CIC-5Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease
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DOI：
10.1038/35042597
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发表时间：
2000-11-16
期刊：
影响因子：
64.8
通讯作者：
Jentsch, TJ
中科院分区：
文献类型：
--
作者：
Piwon, N;Günther, W;Jentsch, TJ
登特氏病是一种X连锁疾病，与尿中低分子量蛋白质、磷酸盐和钙的丢失相关，这通常会导致肾结石（1，2）。它是由ClC-5突变（3）引起的，ClC-5是一种在近端小管内体中表达的肾氯离子通道（4，5）（6，7）。在这里，我们表明小鼠clcn 5基因的破坏通过强烈减少顶端近端小管内吞作用而导致蛋白尿。受体介导的和液相内吞作用都受到影响，顶端转运蛋白NaPi-2和NHE 3的内化减慢。然而，在稳态下，这两种蛋白质从质膜重新分布到细胞内囊泡。这可能是由于观察到的肾小管内吞PTH减少而引起的管腔甲状旁腺激素（PTH）受体刺激增加所致。甲状旁腺素浓度的上升也会刺激25（OH）维生素D-3羟基化为活性激素。然而，这被前体25（OH）维生素D-3的尿液损失所抵消。这两种相反的作用之间的平衡，这两种作用都是继发于近端肾小管内吞作用的缺陷，可能决定是否会有高钙尿症和肾结石。
Dent's disease is an X-linked disorder associated with the urinary loss of low-molecular-weight proteins, phosphate and calcium, which often leads to kidney stones(1,2). It is caused by mutations(3) in ClC-5, a renal chloride channel(4,5) that is expressed in endosomes of the proximal tubule(6,7). Here we show that disruption of the mouse clcn5 gene causes proteinuria by strongly reducing apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed. At steady state, however, both proteins are redistributed from the plasma membrane to intracellular vesicles. This may be caused by an increased stimulation of luminal parathyroid hormone (PTH) receptors owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also stimulate the hydroxylation of 25(OH) vitamin D-3 to the active hormone. However, this is counteracted by a urinary loss of the precursor 25(OH) vitamin D-3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determines whether there will be hypercalciuria and kidney stones.