Intestinal calcium absorption: Molecular vitamin D mediated mechanisms.
Rickets and hyperparathyroidism caused by a defective Vitamin D receptor (VDR) can be prevented in humans and animals by high calcium intake, suggesting that intestinal calcium absorption is critical for 1,25(OH)(2) vitamin D [1,25-(OH)(2)D(3)] action on calcium homeostasis. We assessed the rate of serum (45)Ca accumulation within 10 min after oral gavage in two strains of VDR-knock out (KO) mice (Leuven and Tokyo KO) and observed a threefold lower area under the curve in both KO-strains. Moreover, we evaluated the expression of intestinal candidate genes, belonging to a new class of calcium channels (TRPV), involved in transcellular calcium transport. The calcium transport protein ECaC2 was more abundantly expressed at mRNA level than ECaC1 in duodenum, but both were considerably reduced (ECaC2 > 90%, ECaC1 > 60%) in the two VDR-KO strains on a normal calcium diet. Calbindin-D(9K) expression was only significantly decreased in the Tokyo KO, whereas PMCA(1b) expression was normal in both VDR-KOs. In Leuven wild type mice, a high calcium diet inhibited (> 90%), and 1,25(OH)(2)D(3) or low calcium diet induced (sixfold) duodenal ECaC2 expression and, to a lesser degree, ECaC1 and calbindin-D(9K) expression. In Leuven KO mice, however, high or low calcium intake decreased calbindin-D(9K) and PMCA(1b) expression, whereas both ECaC mRNA expressions remained consistently low on any diet. These results suggest that the expression of the novel duodenal epithelial calcium channels (in particular ECaC2 or TRPV6) is strongly vitamin D dependent and that calcium influx, probably interacting with calbindin-D(9K), should be considered as a rate-limiting step in the process of vitamin D dependent active calcium absorption.
Bouillon
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R
Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Onderwijs en Navorsing, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Roger.Bouillon@med.kuleuven.ac.be
Van Cromphaut
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S
Carmeliet
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G
D000818:Animals; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D050916:TRPV Cation Channels; D014807:Vitamin D / Q000378:metabolism*
D015220:Calcium Channels; D018167:Receptors, Calcitriol; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; C492240:Trpv5 protein, mouse; D014807:Vitamin D; D002118:Calcium