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ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease.

Nature | Nov 16, 2000

http://www.ncbi.nlm.nih.gov/pubmed/11099045

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.

Pubmed ID: 11099045 RIS Download

Mesh terms: Animals | Carrier Proteins | Chloride Channels | Disease Models, Animal | Endocytosis | Female | Genetic Linkage | Kidney Diseases | Kidney Tubules, Proximal | Male | Mice | Mice, Inbred C57BL | Parathyroid Hormone | Proteinuria | Receptors, Parathyroid Hormone | Sodium-Hydrogen Antiporter | Sodium-Phosphate Cotransporter Proteins | Symporters | X Chromosome

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