Duodenal calcium absorption in vitamin D receptor-knockout mice: Functional and molecular aspects
Duodenal calcium absorption in vitamin D receptor-knockout mice: Functional and molecular aspects
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DOI：
10.1073/pnas.231474698
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发表时间：
2001-11-06
影响因子：
11.1
通讯作者：
Carmeliet, G
中科院分区：
文献类型：
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作者：
Van Cromphaut, SJ;Dewerchin, M;Carmeliet, G
维生素D受体（VDR）缺陷引起的佝偻病和甲状旁腺功能亢进症可以通过高钙摄入在人类和动物中预防，这表明肠道钙吸收对于1，25（OH）（2）维生素D [1，25（OH）（2）D-3]对钙稳态的作用至关重要。我们评估了两种VDR基因敲除（KO）小鼠（Leuven和Tokyo KO）经口灌胃10分钟内血清Ca-45蓄积率，并观察到两种KO小鼠的曲线下面积降低3倍。此外，我们评估了参与跨细胞钙转运的肠道候选基因的表达。钙转运蛋白1（CaT 1）在十二指肠中的mRNA水平比上皮钙通道（ECaC）表达更丰富，但在正常钙饮食的两个VDR-KO菌株中，两者均显著降低（CaT 1> 90%，ECaC > 60%）。钙结合蛋白-D-9 K表达仅在东京KO中降低，而质膜钙ATP酶（PMCA（1b））表达在两种VDR-KO中均正常。在鲁汶野生型小鼠中，高钙饮食抑制（> 90%）和1，25（OH）（2）D-3注射或低钙饮食诱导（6倍）十二指肠CaT 1表达，并在较小程度上抑制ECaC和钙结合蛋白-D-9 K表达。然而，在Leuven KO小鼠中，高或低钙摄入量降低了钙结合蛋白-D-9 K和PMCA 1b的表达，而CaT 1和ECaC的表达在任何饮食中都保持较低水平。这些结果表明，新的十二指肠上皮钙通道（特别是CaT 1）的表达是强烈的维生素D依赖性的，钙内流，可能与calbinDin-D-9 K相互作用，应被认为是维生素D依赖性的活性钙吸收过程中的限速步骤。
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 Ca-45 accumulation within 10 min of oral gavage in two strains of VDR-knockout (KO) mice (Leuven and Tokyo KO) and observed a 3-fold lower area under the curve in both KO strains. Moreover, we evaluated the expression of intestinal candidate genes involved in transcellular calcium transport. The calcium transport protein1 (CaT1) was more abundantly expressed at mRNA level than the epithelial calcium channel (ECaC) in duodenum, but both were considerably reduced (CaT1 > 90%, ECaC > 60%) in the two VDR-KO strains on a normal calcium diet. Calbindin-D-9K expression was decreased only in the Tokyo KO, whereas plasma membrane calcium ATPase (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 injection or low calcium diet induced (6-fold) duodenal CaT1 expression and, to a lesser degree, ECaC and calbindin-D-9K expression. In Leuven KO mice, however, high or low calcium intake decreased calbindin-D-9K and PMCA1b expression, whereas CaT1 and ECaC expression remained consistently low on any diet. These results suggest that the expression of the novel duodenal epithelial calcium channels (in particular CaT1) 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.