Reference : Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout m...
Scientific journals : Article
Life sciences : Anatomy (cytology, histology, embryology...) & physiology
http://hdl.handle.net/2268/134553
Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice.
English
Devuyst, Olivier [> >]
JOURET, François mailto [Centre Hospitalier Universitaire de Liège - CHU > > Néphrologie >]
Auzanneau, Celine [> >]
Courtoy, Pierre J. [> >]
2005
Nephron. Clinical Practice
99
3
p69-73
Yes (verified by ORBi)
International
1660-2110
1660-2110
Switzerland
[en] Animals ; Chloride Channels/deficiency/genetics/metabolism ; Endocytosis ; Ion Channel Gating ; Kidney Calculi/genetics/metabolism ; Kidney Tubules, Proximal/metabolism ; Low Density Lipoprotein Receptor-Related Protein-2/metabolism ; Mice ; Mice, Knockout ; Tubulin/metabolism
[en] Dent's disease is a hereditary renal tubular disorder characterized by low-molecular weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of ClC-5, a member of the family of voltage-gated CLC chloride channels. ClC-5 is expressed in part in cells lining the proximal tubule (PT) of the kidney, where it colocalizes with albumin-containing endocytic vesicles belonging to the receptor-mediated endocytic pathway that ensures efficient reabsorption of ultrafiltrated LMW proteins. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of ClC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Analysis of a ClC-5 knockout (KO) mouse model, displaying all the characteristic renal tubular defects of Dent's disease, showed evidence of a severe LMW proteinuria. Cytochemical studies with the endocytic tracer, peroxidase, showed poor transfer into early endocytic vesicles, suggesting that impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. Endocytosis and processing of LMW proteins involve the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. Characterization of the endocytic defect in ClC-5 KO mice revealed that ligands of both megalin and cubilin were affected. The total kidney content of megalin and especially cubilin at the protein level was decreased but, more importantly, using analytical subcellular fractionation and quantitative immunogold labelling we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to ClC-5 inactivation is due at least in part to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent's disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for ClC-5 in the kidney. These studies also provided insights into important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
http://hdl.handle.net/2268/134553
Copyright (c) 2005 S. Karger AG, Basel.

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