title: Activation of the Ca(2+)-sensing receptor increases renal claudin-14 expression and urinary Ca(2+) excretion.
abstract: 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 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 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.
authors.affiliation: Department of Physiology and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Henrik
authors.initials: H
authors.lastname: Dimke
authors.forename: Prajakta
authors.initials: P
authors.lastname: Desai
authors.forename: Jelena
authors.initials: J
authors.lastname: Borovac
authors.forename: Alyssa
authors.initials: A
authors.lastname: Lau
authors.forename: Wanling
authors.initials: W
authors.lastname: Pan
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
mesh_terms: D000818:Animals; D057966:Calcimimetic Agents; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000652:urine*; D002412:Cations / Q000378:metabolism; D002478:Cells, Cultured; D057167:Claudins / Q000378:metabolism*; D053565:Hypercalciuria / Q000209:etiology*; D008138:Loop of Henle / Q000378:metabolism*; D051379:Mice; D009893:Opossums; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D057966:Calcimimetic Agents; D002412:Cations; D057167:Claudins; D044169:Receptors, Calcium-Sensing; D002117:Calcitriol; D002118:Calcium; C422064:claudin 14