Calcitriol controls the epithelial calcium channel in kidney

The recently cloned epithelial Ca2+ channel (ECaC), which is expressed prim arily in 1,25-dihydroxyvitamin D-3 (1,25(0H)(2)D-3)-responsive Ca2+-transpo rting epithelia, is postulated to constitute the rate-limiting step in acti ve Ca2+ reabsorption. In the present study, the effect of 1,25(OH)(2)D-3 wa s investigated on ECaC mRNA and protein levels in kidneys of rats that were raised on a vitamin D-depleting diet. This diet decreased the serum 1,25(O H)(2)D-3 concentration significantly, which was accompanied by a marked dro p in serum Ca2+ level. Both 1,25(OH)(2)D-3 and Ca2+ levels were normalized within 48 h after 1,25(OH)(2)D-3 administration. In 1,25(OH)(2)D-3-deficien t rats, ECaC mRNA and protein levels of the kidney cortex were significantl y decreased compared with the repleted animals, suggesting that 1,25(OH)(2) D-3 exerts its stimulatory effect on Ca2+ reabsorption via increased ECaC e xpression. In agreement with this observation, the elucidated human ECaC pr omoter contains several consensus vitamin D-responsive elements. ECaC was r estricted to the apical membrane of the distal part of the distal convolute d and the connecting tubule. This conclusion was based on only minor overla p with the localization of the thiazide-sensitive NaCl co-transporter and c omplete co-localization with the 1,25(OH)(2)D-3-dependent Ca2+ binding prot ein, calbindin-D-28K In conclusion, ECaC, present in the distal part of the nephron, is an important target for 1,25(OH)(2)D-3-mediated Ca2+ reabsorpt ion.