The claudin-16 channel gene is transcriptionally inhibited by 1,25-dihydroxyvitamin D

摘要: New Findings What is the central question of this study? In kidney, bulk filtered Mg2+ reabsorbed in thick ascending limb by paracellular conductance, mediated tight junction protein, claudin-16, which encoded gene CLDN16. The role 1,25-dihydroxyvitamin D [1,25(OH)2VitD] renal handling unclear. We aimed to explore molecular mechanisms underlying effect 1,25(OH)2VitD on claudin-16-mediated transport. What main finding and its importance? Paracellular, transport transcriptionally repressed 1,25(OH)2VitD, probably via a Ca2+-sensing receptor-dependent mechanism. This may serve as an adaptive mechanism 1,25(OH)2VitD-induced enteric hyperabsorption dietary Mg2+. Magnesium CLDN16-encoded claudin-16. However, have shown that depletion increases inhibits CLDN16 transcription. now explored further transport. Adult mice received parenteral or combined with either high-Mg2+ low-Mg2+ diets. Administration enhanced urinary excretion Ca2+. also increased receptor (CaSR) mRNA decreased claudin-16 claudin-19 but did not affect claudin-2 mRNA. reversed expected increase Mg2+-depleted animals. Comparably treated HEK 293 cells showed similar changes mRNA, alter TRPM6 channel. A luciferase reporter vector containing 2.5 kb 5′-flanking DNA sequence from human (hCLDN16) was transfected into OK cells. hCLDN16 promoter activity modestly markedly inhibited coexpressing CaSR. Coexpression dominant-negative CaSR completely abolished inhibition 1,25(OH)2VitD. decrease attenuated In conclusion, expression sensitive Mg2+. response intestinal absorption.