Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Abstract

The vitamin D receptor (VDR) is a nuclear transcription factor responsible for mediating the biological activities of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Renal and parathyroid gland VDR content is an important factor in calcium homeostasis, vitamin D metabolism, and the treatment of secondary hyperparathyroidism and renal osteodystrophy. In these tissues, VDR expression is highly regulated by the calcium and vitamin D status. Although 1,25(OH)2D3 up-regulates VDR expression, hypocalcemia and vitamin D deficiency result in drastically reduced expression of the receptor. The generation of 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, which are incapable of endogenously producing 1,25(OH)2D3, has allowed us to investigate the influence of parathyroid hormone (PTH) on VDR expression independent of PTHmediated increases in 1,25(OH)2D3. Administration of human PTH (1-34) (110 g͞kg per day) for 48 h reduced renal VDR levels from 515 to 435 fmol͞mg protein (15%, P < 0.03) in wild-type mice. In the 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, PTH administration strongly reduced renal VDR levels, from 555 to 394 fmol͞mg protein (29%, P < 0.001). These results demonstrate that PTH is a potent down-regulator of VDR expression in vivo. The biological response to 1,25(OH) 2 D 3 is directly related to the VDR content of target tissues (6, 7). Thus, the regulation of receptor expression is a critical determinant of hormone activity. The VDR has been shown to be developmentally regulated, expressed in a tissue-specific manner, and regulated by a variety of physiological factors and hormones (8). It is well established that 1,25(OH) 2 D 3 can stimulate receptor expression in the kidney and parathyroid gland while having minimal influence on intestinal VDR expression (9-13). Several studies also have noted a positive correlation between calcium and VDR expression. Hypocalcemia induced by dietary calcium restriction dramatically reduces renal VDR levels and prevents 1,25(OH) 2 D 3 from increasing VDR expression (14-16). Reduced dietary calcium also has been associated with diminished VDR mRNA in avian and rat parathyroid gland (11,12). If left untreated, renal failure with subsequent vitamin D deficiency and hypocalcemia will lead to a decrease in parathyroid gland VDR content and the development of vitamin D resistance (17, 18). The molecular trigger responsible for the hypocalcemia-mediated decline in renal and parathyroid gland VDR content is heretofore unknown.PTH expression is inversely related to serum calcium values (19). Because hypocalcemic animals have high circulating levels of PTH and reduced renal and parathyroid gland VDR expression, we hypothesized that PTH may down-regulate VDR expression. Previous investigations into PTH-mediated regulation of VDR expression yielded mixed results. A PTH-mediated increase of VDR and VDR mRNA was reported in osteoblastlike UMR-106 cells (20, 21), whereas a PTH-mediated decrease in VDR and its transcript was reported in ROS 17͞2.8 osteoblast cells (22). In vivo, osmotic PTH adm...

Ovariectomy worsens secondary hyperparathyroidism in mature rats during low-Ca diet

“…In contrast, circulating PTH levels in sham female rats were not upregulated in response to LCD as usually observed in male animals. Our interpretation is consistent with the recent report by Healy et al (21) in which PTH downregulates renal VDR expression in mice. It remains unclear how ovariectomy alone may induce renal VDR expression, as it cannot be accounted for by the level of circulating PTH or 1,25(OH) 2 D 3 in OVX rats.…”

Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38α MAPK

“…This prior study suggested that high [Ca 2ϩ ] e treatment in HK-2G cells is counter-regulatory to the effects of PTH on VDR. These in vitro changes in VDR mirror the exact scenario that is reflective of in vivo renal VDR regulation that occur during hypo-and hypercalcemia conditions (47,51,52). It will be interesting to examine the dual impact of Ca versus PTH signaling in HK-2G cells with regard to molecular components of renal vitamin D metabolism.…”

Dietary Calcium and 1,25-Dihydroxyvitamin D3 Regulate Transcription of Calcium Transporter Genes in Calbindin-D9k Knockout Mice

“…Parathyroid hormone (PTH) is responsible for maintaining the serum level of calcium. It acts in concert with 1,25-(OH)2D3 to increase bone resorption and renal reabsorption of calcium [26,27]. As a form of negative feedback regulation, 1,25-(OH)2D3 decreases PTH levels by negative regulation of the PTH gene [28].…”