ArticleProceedings of the National Academy of Sciences of the United States of America2003
Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers, 1 of them a synthesis that pooled it.
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Who cites it
123 citing papers in PubMed, 1 synthesis or guideline pooled it, 317 citations in OpenAlex.
- Dent disease: clinical practice recommendations.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Guideline
- Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.The Journal of clinical investigation · 2020Trial
- Vitamin D binding protein in ventral CA3 of the hippocampus drives stress-induced depression.Science advances · 2026Article
- Severe growth retardation in Dent disease: a case report of a novel OCRL variant.CEN case reports · 2026Article
- Megalin: from structure to function.Nature reviews. Nephrology · 2026Review
- Morphofunctional characterization of the ClC-5 chloride channel in the frog's kidney.Histochemistry and cell biology · 2026Article
- Article
- Proximity Labeling Reveals How Lrp2 Interacts with the Endocytic Machine.Journal of proteome research · 2026Article
- Molecular Basis of Rare Inherited Tubulopathies of the Kidney: A Primer for Clinicians.International journal of molecular sciences · 2026Review
- Clinical and Genetic Insights Into Isolated Proteinuria WithKidney international reports · 2026Article
- Albumin overload reduces CFTR and V-ATPase expression and impairs albumin endocytosis and degradation in a renal proximal tubule cell line.Frontiers in pharmacology · 2026Article
- Endosomal 2Cl-/H+ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density.Brain : a journal of neurology · 2025Article
- Unprecedented coexistence of Dent's disease type 1 and Wilson's disease in a two-year-old Chinese boy: implications for precision medicine.BMC nephrology · 2025Article
- Transferrin receptors.Experimental & molecular medicine · 2025Review
- Protein handling in kidney tubules.Nature reviews. Nephrology · 2025Review
- TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.Journal of the American Society of Nephrology : JASN · 2025Article
- Review
- To treat or not to treat: CUBN-associated persistent proteinuria.Kidney research and clinical practice · 2024Article
- The Apical Endocytic-Lysosomal Apparatus in CLCN5 Mutations with Phenotypic-Genotypic Correlations in Three Cases.International journal of molecular sciences · 2024Article
- Emerging roles of proximal tubular endocytosis in renal fibrosis.Frontiers in cell and developmental biology · 2023Review
63 more citing papers are in PubMed but not listed here.
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9 authors at 1 institution in 1 country.
Funding
Abstract
Loss of the renal endosome-associated chloride channel, ClC-5, in Dent's disease and knockout (KO) mice strongly inhibits endocytosis of filtered proteins by kidney proximal tubular cells (PTC). The underlying mechanism remains unknown. We therefore tested whether this endocytic failure could primarily reflect a loss of reabsorption by the multiligand receptors, megalin, and cubilin, caused by a trafficking defect. Impaired protein endocytosis in PTC of ClC-5 KO mice was demonstrated by (i) a major decreased uptake of injected 125I-beta 2-microglobulin, but not of the fluid-phase tracer, FITC-dextran, (ii) reduced labeling of endosomes by injected peroxidase and for the endogenous megalin/cubilin ligands, vitamin D- and retinol-binding proteins, and (iii) urinary appearance of low-molecular-weight proteins and the selective cubilin ligand, transferrin. Contrasting with preserved mRNA levels, megalin and cubilin abundance was significantly decreased in kidney extracts of KO mice. Percoll gradients resolving early and late endosomes (Rab5a, Rab7), brush border (villin, aminopeptidase M), and a dense peak comprising lysosomes (acid hydrolases) showed a disappearance of the brush border component for megalin and cubilin in KO mice. Quantitative ultrastructural immunogold labeling confirmed the overall decrease of megalin and cubilin in PTC and their selective loss at the brush border. In contrast, total contents of the rate-limiting endocytic catalysts, Rab5a and Rab7, were unaffected. Thus, impaired protein endocytosis caused by invalidation of ClC-5 primarily reflects a trafficking defect of megalin and cubilin in PTC.
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