Dyo

FIGURE 16 Actions of 1,25(OH)2D3 on intestinal transport of calcium. VDR, vitamin D receptor; CaT1, calcium transporter 1; ECaC, epithelial calcium transporter; CaB, calbindin.

Duodenal Epithelial Cell

FIGURE 16 Actions of 1,25(OH)2D3 on intestinal transport of calcium. VDR, vitamin D receptor; CaT1, calcium transporter 1; ECaC, epithelial calcium transporter; CaB, calbindin.

times as much 1,25(OH)2D3 is needed to mobilize calcium and phosphate. The molecular site(s) of cooperative interaction of these two hormones in osteoblasts is(are) not known.

Actions on Kidney

When given to vitamin D-deficient subjects, 1,25(OH)2D3 increases reabsorption of both calcium and phosphate. The effects on phosphate reabsorption are probably indirect. PTH secretion is increased in vitamin D deficiency (see later discussion), and hence tubular reabsorption of phosphate is restricted. Replenishment of 1,25(OH)2D3 decreases the secretion of PTH and thus allows proximal tubular reabsorption of phosphate to increase. Effects of 1,25(OH)2D3 on calcium reabsorption are probably direct. Specific receptors for 1,25(OH)2D3 are found in the distal nephron, probably in the same cells in which PTH stimulates calcium uptake. These cells also express the same vitamin D-dependent calcium-binding protein, calbindin, that is found in intestinal cells, and calbindin is likely to play the same role in renal tubular cells as in intestinal epithelium. It is unlikely that 1,25(OH)2D3 regulates calcium balance on a minute-to-minute basis. Instead, it may act in a permissive way to support the actions of PTH, which is the primary regulator. The molecular basis for this interaction has not been elucidated.

Actions on the Parathyroid Glands

The chief cells of the parathyroid glands are physiologic targets for 1,25(OH)2D3 and respond to it in a manner that is characteristic of negative feedback. In this case, negative feedback is exerted at the level of synthesis rather than secretion. The promoter region of the PTH gene contains a vitamin D response element. Binding of the liganded receptor suppresses transcription of the gene and leads to a rapid decline in the preproPTH mRNA. Because the chief cells store relatively little hormone, decreased synthesis rapidly leads to decreased secretion. In a second negative feedback action, 1,25(OH)2D3 indirectly decreases PTH secretion by virtue of its actions to increase plasma calcium concentration. Consistent with the crucial role of calcium in regulating PTH secretion, the negative feedback effects of 1,25(OH)2D3

on PTH synthesis are modulated by the plasma calcium concentration. Nuclear receptors for 1,25(OH)2D3 are down-regulated when the plasma calcium concentration is low and up-regulated when it is high.

Regulation of 1,25(OH)2D3 Production

As true of any hormone, the concentration of 1,25(OH)2D3 in blood must be appropriate for prevailing physiologic circumstances if it is to exercise its proper role in maintaining homeostasis. Production of 1,25(OH)2D3 is subject to feedback regulation in a fashion quite similar to that of other hormones. The most important regulatory step is the hydroxylation of carbon 1 by cells in the proximal tubules of the kidney. The rate of this reaction is determined by the availability of the requisite P450 enzyme, which has a half-life of only about 2-4 hr. Regulation of synthesis of 1,25(OH)D3 is achieved by regulating transcription of the gene that codes for the 1a-hydroxylase.rate of enzyme. Several cyclic AMP response elements (CRE) are present in its promoter region. PTH activates transcription of the 1a-hydroxylase gene through increasing production of cyclic AMP, activation of protein kinase A, and phos-phorylation of CREB. Activation of protein kinase C through the IP3-DAG second messenger system also appears to play some role in up-regulation of this enzyme. In the absence of PTH, the concentration of 1a-hydroxylase in renal cells quickly falls. A major component of the negative feedback system is the powerful inhibitory effect of 1,25(OH)2D3 to suppress PTH gene expression in the parathyroid chief cells.

Through a "short" feedback loop, 1,25(OH)2D3 acts as a negative feedback inhibitor of its own production by rapidly down-regulating 1a-hydroxylase expression. At the same time, 1,25(OH)D3 up-regulates the enzyme that hydroxylates vitamin D metabolites on carbon 24 to produce 24,25(OH)2D3 or 1,24,25(OH)3D3. Hydroxylation at carbon 24 is the initial reaction in the degradative pathway that culminates in the production of calcitroic acid, the principal biliary excretory product of vitamin D. Up-regulation of the 24 hydroxylase by 1,25(OH)D3 is not confined to the kidney, but is also seen in all 1,25(OH)D3 target cells.

Urine

FIGURE 17 Regulation of 1a,25-dihydroxycholecalciferol synthesis. Solid arrows indicate stimulation; dashed arrows represent inhibition.

Urine

FIGURE 17 Regulation of 1a,25-dihydroxycholecalciferol synthesis. Solid arrows indicate stimulation; dashed arrows represent inhibition.

Finally, the results of its actions, increased calcium and phosphate concentrations in blood, directly or indirectly silence the two activators of 1,25(OH)2D3 production, PTH, and low phosphate. The regulation of 1,25(OH)2D3 production is summarized in Fig. 17.

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