Calcitriol controls the epithelial calcium channel in kidney.
The recently cloned epithelial Ca2+ channel (ECaC), which is expressed primarily in 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-responsive Ca2+ -transporting epithelia, is postulated to constitute the rate-limiting step in active Ca2+ reabsorption. In the present study, the effect of 1,25(OH)(2)D(3) was 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(OH)(2)D(3) concentration significantly, which was accompanied by a marked drop 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)-deficient rats, ECaC mRNA and protein levels of the kidney cortex were significantly decreased compared with the repleted animals, suggesting that 1,25(OH)(2)D(3) exerts its stimulatory effect on Ca2+ reabsorption via increased ECaC expression. In agreement with this observation, the elucidated human ECaC promoter contains several consensus vitamin D-responsive elements. ECaC was restricted to the apical membrane of the distal part of the distal convoluted and the connecting tubule. This conclusion was based on only minor overlap with the localization of the thiazide-sensitive NaCl co-transporter and complete co-localization with the 1,25(OH)(2)D(3)-dependent Ca2+ binding protein, 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+ reabsorption.
Hoenderop
Joost G J
JGJ
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Müller
Dominik
D
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
VAN DER Kemp
Annemiete W C M
AWCM
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Hartog
Anita
A
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Suzuki
Makoto
M
Department of Pharmacology, Jichi Medical School, Tochigi, Japan.
Ishibashi
Kenichi
K
Department of Pharmacology, Jichi Medical School, Tochigi, Japan.
Imai
Masashi
M
Department of Pharmacology, Jichi Medical School, Tochigi, Japan.
Sweep
Fred
F
Department of Endocrinology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Willems
Peter H G M
PHGM
Department of Biochemistry, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Os
Carel H VAN
CHV
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Bindels
René J M
RJM
Department of Cell Physiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D064026:Calbindins; D002117:Calcitriol / Q000494:pharmacology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D006706:Homeostasis / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D050916:TRPV Cation Channels; D014018:Tissue Distribution; D014808:Vitamin D Deficiency
D064026:Calbindins; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; C492241:TRPV5 protein, rat; D002117:Calcitriol; D002118:Calcium