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首页> 外文期刊>Nature >ClC-5 Cl~- -channel disruption impairs endocytosis in a mouse model for Dent's disease
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ClC-5 Cl~- -channel disruption impairs endocytosis in a mouse model for Dent's disease

机译：ClC-5 Cl〜-通道破坏削弱了登特氏病小鼠模型的内吞作用

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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. It is caused by mutations3 in ClC-5, a renal chloride channel that is expressed in endosomes of the proximal tubule. 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 hyper-calciuria and kidney stones.
机译：登特氏病是与X连锁的疾病，与低分子量蛋白质，磷酸盐和钙的尿流失有关，常常导致肾结石。它是由ClC-5中的突变3引起的，ClC-5是在近端小管的内体中表达的肾氯化物通道。在这里，我们显示破坏小鼠clcn5基因会通过强烈减少顶端近端肾小管内吞作用而引起蛋白尿。受体介导的和细胞相的内吞作用均受到影响，并且顶端转运蛋白NaPi-2和NHE3的内在化减慢。然而，在稳定状态下，两种蛋白质都从质膜重新分布到细胞内囊泡。这可能是由于对腔内甲状旁腺激素（PTH）受体的刺激增加所致，原因是观察到的PTH的肾小管内吞作用减少。腔内PTH浓度的增加也应刺激25（OH）维生素D_3羟基化为活性激素。然而，这通过前体25（OH）维生素D_3的尿失而抵消。这些对立的作用之间的平衡（两者都是继发于近端肾小管内吞作用的缺陷）可能决定了是否会出现高钙化和肾结石。

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