ClC-5 Cl- -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. 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.
Piwon
N
N
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Germany.
Günther
W
W
Schwake
M
M
Bösl
M R
MR
Jentsch
T J
TJ
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D004705:Endocytosis; D005260:Female; D008040:Genetic Linkage; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000378:metabolism; D011507:Proteinuria; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D014960:X Chromosome
C097503:CLC-5 chloride channel; D002352:Carrier Proteins; D018118:Chloride Channels; D010281:Parathyroid Hormone; D018016:Receptors, Parathyroid Hormone; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters