Format

Send to

Choose Destination
Kidney Int. 2018 Mar;93(3):580-588. doi: 10.1016/j.kint.2017.08.029. Epub 2017 Nov 10.

Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria.

Author information

1
Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany. Electronic address: tilman.breiderhoff@charite.de.
2
Institute of Physiology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
3
Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
4
Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
5
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
6
Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: dominik.mueller@charite.de.
7
Institute of Physiology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. Electronic address: m.bleich@physiologie.uni-kiel.de.

Abstract

The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.

KEYWORDS:

calcium; claudin; magnesium; paracellular pathway; thick ascending limb; tight junction

PMID:
29129401
DOI:
10.1016/j.kint.2017.08.029
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center