Faculty Opinions recommendation of Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism.

FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(−/−) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(−/−) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1α-hydroxylase mRNA levels in VDR(−/−) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(−/−) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1α-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.

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Antenatal endotoxin disrupts lung vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase expression in the developing rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2015 ◽

2015 ◽

Vol 309 (9) ◽

pp. L1018-L1026 ◽

Cited By ~ 11

Author(s):

Erica Mandell ◽

Gregory J. Seedorf ◽

Sharon Ryan ◽

Jason Gien ◽

Scott D. Cramer ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Fetal Lung ◽

Tube Formation ◽

Late Gestation ◽

Lung Growth ◽

Specific Expression ◽

Vitamin D Metabolism ◽

Fetal Sheep ◽

Hydroxyvitamin D

Vitamin D [vit D; 1,25-(OH)2D] treatment improves survival and lung alveolar and vascular growth in an experimental model of bronchopulmonary dysplasia (BPD) after antenatal exposure to endotoxin (ETX). However, little is known about lung-specific 1,25-(OH)2D3 regulation during development, especially regarding maturational changes in lung-specific expression of the vitamin D receptor (VDR), 1α-hydroxylase (1α-OHase), and CYP24A1 during late gestation and the effects of antenatal ETX exposure on 1,25-(OH)2D3 metabolism in the lung. We hypothesized that vit D regulatory proteins undergo maturation regulation in the late fetal and early neonatal lung and that prenatal exposure to ETX impairs lung growth partly through abnormal endogenous vit D metabolism. Normal fetal rat lungs were harvested between embryonic day 15 and postnatal day 14. Lung homogenates were assayed for VDR, 1α-OHase, and CYP24A1 protein contents by Western blot analysis. Fetal rats were injected on embryonic day 20 with intra-amniotic ETX, ETX + 1,25-(OH)2D3, or saline and delivered 2 days later. Pulmonary artery endothelial cells (PAECs) from fetal sheep were assessed for VDR, 1α-OHase, and CYP24A1 expression after treatment with 25-(OH)D3, 1,25-(OH)2D3, ETX, ETX + 25-(OH)D3, or ETX + 1,25-(OH)2D3. We found that lung VDR, 1α-OHase, and CYP2741 protein expression dramatically increase immediately before birth ( P < 0.01 vs. early fetal values). Antenatal ETX increases CYP24A1 expression ( P < 0.05) and decreases VDR and 1α-OHase expression at birth ( P < 0.001), but these changes are prevented with concurrent vit D treatment ( P < 0.001). ETX-induced reduction of fetal PAEC growth and tube formation and lung 1α-OHase expression are prevented by vit D treatment ( P < 0.001). We conclude that lung VDR, 1α-OHase, and CYP24A1 protein content markedly increase before birth and that antenatal ETX disrupts lung vit D metabolism through downregulation of VDR and increased vit D catabolic enzyme expression, including changes in developing endothelium. We speculate that endogenous vitamin D metabolism modulates normal fetal lung development and that prenatal disruption of vit D signaling may contribute to impaired postnatal lung growth at least partly through altered angiogenic signaling.

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Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism

AJP Renal Physiology ◽

10.1152/ajprenal.00474.2004 ◽

2005 ◽

Vol 289 (5) ◽

pp. F1088-F1095 ◽

Cited By ~ 245

Author(s):

Takashi Shimada ◽

Yuji Yamazaki ◽

Motoo Takahashi ◽

Hisashi Hasegawa ◽

Itaru Urakawa ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Calcium Supplementation ◽

Mrna Level ◽

Serum Phosphate ◽

Serum Phosphate Level ◽

Phosphate Metabolism ◽

Independent Manner ◽

Vitamin D Metabolism ◽

Induced Changes

FGF23 suppresses both serum phosphate and 1,25-dihydroxyvitamin D [1,25D] levels in vivo. Because 1,25D itself is a potent regulator of phosphate metabolism, it has remained unclear whether FGF23-induced changes in phosphate metabolism were caused by a 1,25D-independent mechanism. To address this issue, we intravenously administered recombinant FGF23 to vitamin D receptor (VDR) null (KO) mice as a rapid bolus injection and evaluated the early effects of FGF23. Administration of recombinant FGF23 further decreased the serum phosphate level in VDR KO mice, accompanied by a reduction in renal sodium-phosphate cotransporter type IIa (NaPi2a) protein abundance and a reduced renal 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) mRNA level. Thus FGF23-induced changes in NaPi2a and 1αOHase expression are independent of the 1,25D/VDR system. However, 24-hydroxylase (24OHase) mRNA expression remained undetectable by the treatment with FGF23. We also analyzed the regulatory mechanism for FGF23 expression. The serum FGF23 level was almost undetectable in VDR KO mice, whereas dietary calcium supplementation significantly increased circulatory levels of FGF23 and its mRNA abundance in bone. This finding indicates that calcium is another determinant of FGF23 production that occurs independently of the VDR-mediated mechanism. In contrast, dietary phosphate supplementation failed to induce FGF23 expression in the absence of VDR, whereas marked elevation in circulatory FGF23 was observed in wild-type mice fed with a high-phosphate diet. Taken together, FGF23 works, at least in part, in a VDR-independent manner, and FGF23 production is also regulated by multiple mechanisms involving VDR-independent pathways.

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Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21249626 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9626

Author(s):

Adolfo I. Ruiz-Ballesteros ◽

Mónica R. Meza-Meza ◽

Barbara Vizmanos-Lamotte ◽

Isela Parra-Rojas ◽

Ulises de la Cruz-Mosso

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Lupus Erythematosus ◽

Association Studies ◽

Genetic Association Studies ◽

Serum Levels ◽

Nucleotide Polymorphisms ◽

Vitamin D Metabolism ◽

Single Nucleotide ◽

High Prevalence

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

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