Publication Date:
2013-03-16
Description:
Kidney stones are a prevalent clinical condition imposing a large economic burden on the healthcare system. Hypercalciuria remains the major risk factor for development of a Ca 2+ -containing stone. The kidney's ability to alter Ca 2+ excretion in response to changes in serum Ca 2+ is in part mediated by the Ca 2+ -sensing receptor (CaSR). Recent studies revealed renal claudin-14 (Cldn14) expression localized to the thick ascending limb (TAL) and its expression to be regulated via the CaSR. We find that Cldn14 expression is increased by high dietary Ca 2+ intake and by elevated serum Ca 2+ levels induced by prolonged 1,25-dihydroxyvitamin D 3 administration. Consistent with this, activation of the CaSR in vivo via administration of the calcimimetic cinacalcet hydrochloride led to a 40-fold increase in Cldn14 mRNA. Moreover, overexpression of Cldn14 in two separate cell culture models decreased paracellular Ca 2+ flux by preferentially decreasing cation permeability, thereby increasing transepithelial resistance. These data support the existence of a mechanism whereby activation of the CaSR in the TAL increases Cldn14 expression, which in turn blocks the paracellular reabsorption of Ca 2+ . This molecular mechanism likely facilitates renal Ca 2+ losses in response to elevated serum Ca 2+ . Moreover, dysregulation of the newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.
Print ISSN:
1931-857X
Electronic ISSN:
1522-1466
Topics:
Medicine
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