1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine
1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine
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DOI：
10.1113/jp280345
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发表时间：
2020-12-08
影响因子：
5.5
通讯作者：
Wagner, Carsten A.
中科院分区：
文献类型：
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作者：
Hernando, Nati;Pastor-Arroyo, Eva Maria;Wagner, Carsten A.
关键点磷酸盐的肠道吸收通过主要由NaPi-IIb/Slc 34 a2介导的主动/跨细胞途径和特征不明显的被动/细胞旁途径进行。肠道磷酸盐吸收和NaPi-IIb的表达受到1，25（OH）（2）维生素D-3的刺激，但NaPi-IIb是否是激素控制下的唯一靶点仍不清楚。我们报告了1，25（OH）（2）维生素D-3的野生型小鼠导致预期的增加磷酸盐在空肠中的主动转运，而不改变细胞旁流量。相反，同样的治疗未能改变尿中缺乏Slc 34 a2缺陷小鼠的磷酸盐转运。在两种基因型中，1，25（OH）（2）维生素D-3诱导了相似的高磷酸盐尿反应和血浆FGF 23和PTH水平的变化。而1，25（OH）（2）维生素D-3诱导的尿磷酸盐丢失并没有改变血浆磷酸盐，进一步的研究应该调查长期服用是否会导致小鼠体内磷酸盐失衡，导致肠吸收减少。2肠对磷酸盐的吸收受1，25（OH）（2）维生素D-3刺激。至少有两种不同的机制是磷酸盐在肠道中吸收的基础，一种是需要Na+/磷酸盐协同转运蛋白NaPi-IIb/Slc 34 a2的主动跨细胞转运，另一种是表征不佳的细胞旁被动途径。1，25（OH）（2）维生素D-3刺激NaPi-IIb的表达和功能，NaPi-IIb的缺失会减少肠道对磷酸盐的吸收。然而，NaPi-IIb是否是1，25（OH）（2）维生素D-3激素调节的唯一靶点仍然未知。在这里，我们比较了腹膜内注射1，25（OH）（2）维生素D-3（2天，每天一次）对野生型和卵巢特异性Slc 34 a2缺陷小鼠的影响，并分析了磷酸盐吸收的跨细胞途径和细胞旁途径。我们发现，治疗刺激磷酸盐的主动运输仅在空肠的野生型小鼠，虽然NaPi-IIb蛋白表达上调空肠和回肠。相比之下，1，25（OH）（2）维生素D-3给药对Slc 34 a2缺陷小鼠没有影响，表明该激素特异性调节NaPi-IIb表达。在两组中，1，25（OH）（2）维生素D-3引起血浆成纤维细胞生长因子23（FGF 23）的预期增加和甲状旁腺激素（PTH）的减少。治疗导致两种基因型的高磷酸盐尿症（和高钙尿症），尽管小鼠保持正常磷酸盐血症。虽然增加的肠吸收和更高的FGF 23可以在野生型中触发高磷酸尿反应，但只有更高的FGF 23可以解释Slc 34 a2缺陷小鼠中的肾反应。因此，1，25（OH）（2）维生素D-3通过作用于主要由NaPi-IIb介导的主动跨细胞途径而刺激肠磷酸盐吸收，而细胞旁途径似乎不受影响。
Key pointsIntestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi-IIb/Slc34a2 and a poorly characterized passive/paracellular pathway.Intestinal phosphate absorption and expression of NaPi-IIb are stimulated by 1,25(OH)(2) vitamin D-3 but whether NaPi-IIb is the only target under hormonal control remains unknown.We report that administration of 1,25(OH)(2) vitamin D-3 to wild-type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal-depleted Slc34a2-deficient mice.In both genotypes, 1,25(OH)(2) vitamin D-3 induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH.While urinary phosphate loss induced by administration of 1,25(OH)(2) vitamin D-3 did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption.Intestinal absorption of phosphate is stimulated by 1,25(OH)(2) vitamin D-3. At least two distinct mechanisms underlie phosphate absorption in the gut, an active transcellular transport requiring the Na+/phosphate cotransporter NaPi-IIb/Slc34a2, and a poorly characterized paracellular passive pathway. 1,25(OH)(2) vitamin D-3 stimulates NaPi-IIb expression and function, and loss of NaPi-IIb reduces intestinal phosphate absorption. However, it is remains unknown whether NaPi-IIb is the only target for hormonal regulation by 1,25(OH)(2) vitamin D-3. Here we compared the effects of intraperitoneal administration of 1,25(OH)(2) vitamin D-3 (2 days, once per day) in wild-type and intestinal-specific Slc34a2-deficient mice, and analysed trans- vs. paracellular routes of phosphate absorption. We found that treatment stimulated active transport of phosphate only in jejunum of wild-type mice, though NaPi-IIb protein expression was upregulated in jejunum and ileum. In contrast, 1,25(OH)(2) vitamin D-3 administration had no effect in Slc34a2-deficient mice, suggesting that the hormone specifically regulates NaPi-IIb expression. In both groups, 1,25(OH)(2) vitamin D-3 elicited the expected increase of plasma fibroblast growth factor 23 (FGF23) and reduction of parathyroid hormone (PTH). Treatment resulted in hyperphosphaturia (and hypercalciuria) in both genotypes, though mice remained normophosphataemic. While increased intestinal absorption and higher FGF23 can trigger the hyperphosphaturic response in wild types, only higher FGF23 can explain the renal response in Slc34a2-deficient mice. Thus, 1,25(OH)(2) vitamin D-3 stimulates intestinal phosphate absorption by acting on the active transcellular pathway mostly mediated by NaPi-IIb while the paracellular pathway appears not to be affected.