Piwon N, Günther W, Schwake M, Bösl M R, Jentsch T J
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Germany.
Nature. 2000 Nov 16;408(6810):369-73. doi: 10.1038/35042597.
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 mutations 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 D3 to the active hormone. However, this is counteracted by a urinary loss of the precursor 25(OH) vitamin D3. 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.
邓特氏病是一种X连锁疾病，与低分子量蛋白质、磷酸盐和钙的尿流失有关，常导致肾结石。它由ClC-5基因突变引起，ClC-5是一种在近端小管内体中表达的肾氯通道。我们在此表明，小鼠clcn5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。受体介导的内吞作用和液相内吞作用均受影响，顶端转运体NaPi-2和NHE3的内化减慢。然而，在稳态时，这两种蛋白质均从质膜重新分布到细胞内囊泡。这可能是由于观察到的甲状旁腺激素（PTH）的肾小管内吞作用降低，导致管腔PTH受体刺激增加所致。管腔PTH浓度的升高也应刺激25（OH）维生素D3羟化为活性激素。然而，这被前体25（OH）维生素D3的尿流失所抵消。这两种相反作用之间的平衡，均继发于近端小管内吞作用缺陷，可能决定是否会出现高钙尿症和肾结石。
