CIC-5Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease

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). H ere we show that disruption of the mouse clcn5 gene causes proteinuria by s trongly reducing apical proximal tubular endocytosis. Both receptor-mediate d and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed. At steady state, however, bo th proteins are redistributed from the plasma membrane to intracellular ves icles. This may be caused by an increased stimulation of luminal parathyroi d hormone (PTH) receptors owing to the observed decreased tubular endocytos is 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 ba lance between these opposing effects, both of which are secondary to the de fect in proximal tubular endocytosis, probably determines whether there wil l be hypercalciuria and kidney stones.