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 stones1,2. It is

caused by mutations3 in ClC-5, a renal chloride channel4,5 that is expressed in endosomes of the proximal tubule6,7. 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. Access through your institution Buy or subscribe This is a preview

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MUTATION IN _SLC34A1_ HAS NO EFFECT IN MINERAL HOMEOSTASIS IN MICE Article Open access 12 April 2022 RELATIONSHIP BETWEEN CLINICAL PHENOTYPE AND IN VITRO ANALYSIS OF 13 NPT2C/SCL34A3 MUTANTS

Article Open access 03 January 2023 TMEM174, A REGULATOR OF PHOSPHATE TRANSPORTER PREVENTS HYPERPHOSPHATEMIA Article Open access 15 April 2022 REFERENCES * Wrong, O. M., Norden, A. G. &

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Google Scholar  Download references ACKNOWLEDGEMENTS We thank G. Boia for technical assistance, P. Gruss for MPI2 ES cells, H. Murer and J. Biber for the NaPi-2 antibody, R. McCluskey for

the megalin antibody, S. Gluck and D. K. Stone for proton pump antibodies, B. Blaner for the antibody against retinol binding protein and M. Haddad for chemical analysis of serum and urine

samples. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Louis-Jeantet Prize for medicine to T.J.J. AUTHOR INFORMATION

Author notes * Nils Piwon and Willy Günther: These authors contributed equally to this work. * Correspondence and requests for materials should be addressed to T.J.J.. AUTHORS AND

AFFILIATIONS * Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Martinistrasse 85, Hamburg, D-20246, Germany Nils Piwon, Willy Günther, Michael Schwake, Michael R.

Bösl & Thomas J. Jentsch Authors * Nils Piwon View author publications You can also search for this author inPubMed Google Scholar * Willy Günther View author publications You can also

search for this author inPubMed Google Scholar * Michael Schwake View author publications You can also search for this author inPubMed Google Scholar * Michael R. Bösl View author

publications You can also search for this author inPubMed Google Scholar * Thomas J. Jentsch View author publications You can also search for this author inPubMed Google Scholar

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_et al._ ClC-5 Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease. _Nature_ 408, 369–373 (2000). https://doi.org/10.1038/35042597 Download citation *

Received: 29 June 2000 * Accepted: 29 September 2000 * Issue Date: 16 November 2000 * DOI: https://doi.org/10.1038/35042597 SHARE THIS ARTICLE Anyone you share the following link with will

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