Activation of the Ca2+-sensing receptor increases renal claudin-14 expression and urinary Ca2+ excretion

摘要

Kidney stones are a prevalent clinical condition imposing a large economic burden on the health-care system. Hypercalciuria remains the major risk factor for development of a Ca²⁺-containing stone. The kidney’s ability to alter Ca²⁺ excretion in response to changes in serum Ca²⁺ is in part mediated by the Ca²⁺-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 Ca²⁺ intake and by elevated serum Ca²⁺ levels induced by prolonged 1,25-dihydroxyvitamin D3 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 Ca²⁺ 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 Ca²⁺. This molecular mechanism likely facilitates renal Ca²⁺ losses in response to elevated serum Ca²⁺. Moreover, dys-regulation of the newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.