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

Abstract

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.

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…The underlying defect was identified as an inability of the tubule cells to perform megalin-mediated uptake of vitamin D metabolites bound to DBP (Plans et al, 2009). The same finding was obtained in mouse models of ClC-5 deficiency (Piwon et al, 2000;Wang et al, 2000).…”

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

“…Indeed, regulation of vesicle acidification by chloride counter-ion flux seems to be a common phenomenon (al Awqati et al 1992). For example, ClC-5 was found on endocytic vesicles of renal cells (Günther et al 1998), and disruption of this channel impaired endocytosis and vesicle acidification (Piwon et al 2000).…”

Molecular Mechanisms of Primary Hypercalciuria

“…Piwon et al (87) disrupted exon 5 and eliminated exon 6 of CLC-5 and substantiated that CLC-5 protein was undetectable by Western blots in kidney, liver, intestine, or testis. Both CLC-5 Ϫ/y (male knockout) and Ϫ/Ϫ (female knockout) animals were normocalcemic, normocalciuric, and hyperphosphaturic.…”