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

Item Type:Article
Title:Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria
Creators Name:Breiderhoff, T. and Himmerkus, N. and Drewell, H. and Plain, A. and Guenzel, D. and Mutig, K. and Willnow, T.E. and Müller, D. and Bleich, M.
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, Animals, Mice
Source:Kidney International
ISSN:0085-2538
Publisher:Elsevier (U.S.A.)
Volume:93
Number:3
Page Range:580-588
Date:March 2018
Official Publication:https://doi.org/10.1016/j.kint.2017.08.029
PubMed:View item in PubMed

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