1,25-Dihydroxyvitamin D3 up-regulates the renal vitamin D receptor through indirect gene activation and receptor stabilization☆
Section snippets
Chemicals
1,25(OH)2D3 was purchased from Tetrionics (Madison, WI). Actinomycin D and cycloheximide were purchased from Sigma (St. Louis, MO).
Mice and diets
Breeding pairs of B6/CBA mice (The Jackson Laboratory) were maintained on chow LabDiet 5015 (PMI Nutrition International, St. Louis). Vitamin D-deficiency was generated by transferring visibly pregnant females into housing in which all fluorescent lighting was shielded, preventing the endogenous production of vitamin D3. These females were fed a 1.20% calcium diet
Dietary calcium and 1,25(OH)2D3 elevate renal VDR and VDR mRNA but have minimal impact on intestinal VDR expression
To study the effect of calcium and 1,25(OH)2D3 on renal and duodenal VDR expression, vitamin D-deficient mice were weaned onto purified diets that contained 0.02 or 0.47% calcium, with or without 50 ng of 1,25(OH)2D3 per day. As shown in Table 1, mice maintained on the 0.02% calcium diets suffered from severe hypocalcemia, even with 50 ng of 1,25(OH)2D3 per day in the diet. Vitamin D-deficient mice maintained on the 0.47% calcium diet were hypocalcemic, whereas mice on the 0.47% calcium diet
Discussion
We have analyzed the regulation of VDR expression by calcium and 1,25(OH)2D3 in mouse kidney and duodenum, and utilized a cell culture model to further our understanding of the basic mechanisms responsible for aspects of renal VDR regulation. Mice fed 50 ng of 1,25(OH)2D3 per day and 0.47% calcium had 5-fold higher levels of renal VDR than mice fed a calcium-restricted diet either with or without 50 ng of 1,25(OH)2D3. Initial reports of VDR up-regulation by 1,25(OH)2D3 were attributed to
Acknowledgments
We thank Jean Prahl for her assistance with the ELISA assays, Eric Danielson for his aid in genotyping, and Wendy Hellwig for her help in the quantification of serum calcium.
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Cited by (43)
Role of vitamin D and vitamin D receptor (VDR) in oral cancer
2019, Biomedicine and PharmacotherapyCitation Excerpt :Maybe the most interesting aspect is the capability of 1,25(OH)2D3 to raise the expression of the VDR gene. Identically, VDR levels autoregulate by 1,25(OH)2D3 over both transcriptional [51–53] and posttranslational [53,54] regulations. In the other case, the ligand interactions with its receptor led to increasing the stability of the VDR protein, of which the mechanism remains to be determined although the studies suggest that several enhancers located within the gene itself directly involved in autoregulation of the VDR gene by 1,25-(OH)2D3.
The impact of VDR expression and regulation in vivo
2018, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :As shown in Fig. 2A, Vdr expression was induced by 1,25(OH)2D3 and PTH in calvaria and by 1,25(OH)2D3 and FGF23 in kidney, whereas it was not significantly changed by hormonal treatments in intestine, a result comparable to our previous findings [25]. It has been shown previously that VDR levels in kidney are decreased under hypocalcemic condition whereas the levels in intestine are not changed [27]. We therefore compared Vdr expression in wildtype mice with Cyp27b1-null mice that display hypocalcemia and secondary hyperparathyroidism due to the loss of ability to produce 1,25(OH)2D3.
Mechanisms and significance of nuclear receptor auto- and cross-regulation
2011, General and Comparative EndocrinologyCitation Excerpt :In animals, autoregulation of the VDR is tissue-specific; e.g., vitamin D3 increases VDR mRNA levels in the kidney (Healy et al., 2003, 2005), parathyroid gland (Naveh-Many et al., 1990) and skin (Zineb et al., 1998), but not in the intestine (Wiese et al., 1992; Zineb et al., 1998; but see Strom et al., 1989). Autoinduction of VDR in the kidney depends on a normal serum calcium level (Healy et al., 2003, 2005). Vitamin D3 causes upregulation of VDR mRNA in cultured osteoblastic cells, which suggests that the gene can be autoinduced in bone (Mahonen and Maenpaa, 1994; Zella et al., 2006, 2010).
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This work was supported by the Wisconsin Alumni Research Foundation.