scholarly journals 1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2204-2214 ◽  
Author(s):  
Janaina S Martins ◽  
Eva S Liu ◽  
W Bruce Sneddon ◽  
Peter A Friedman ◽  
Marie B Demay
Keyword(s):  
Brush Border ◽  
Hormonal Regulation ◽  
Fibroblast Growth Factor 23 ◽  
Term Treatment ◽  
Scaffolding Protein ◽  
Phosphate Reabsorption ◽  
Dihydroxyvitamin D ◽  
Protein Levels ◽  
1,25 Dihydroxyvitamin D ◽  
Long Term Treatment

Abstract Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

scholarly journals The effect of long-term treatment with steroid hormones or tamoxifen on oestrogen receptors (alpha and beta) in the endometrium of ovariectomized cynomolgus macaques

2002 ◽  
Vol 175 (3) ◽  
pp. 673-681 ◽  
Author(s):  
H Wang ◽  
E Isaksson ◽  
B Von Schoultz ◽  
JM Cline ◽  
L Sahlin
Keyword(s):  
Hormone Treatment ◽  
Term Treatment ◽  
Response To Treatment ◽  
Oestrogen Receptors ◽  
Minor Variation ◽  
Protein Levels ◽  
Long Term Treatment ◽  
High Level ◽  
Er Alpha

The effects of oestrogen are mediated by two specific intracellular receptors, oestrogen receptors (ER) alpha and beta, which function as ligand-activated transcriptional regulators. Ovariectomized macaques (Macaca fascicularis) were used to study the regulation of ERalpha and ERbeta in the endometrium by immunohistochemistry and in situ hybridization after long-term hormone treatment. Animals were treated continuously for 35 Months with either conjugated equine oestrogen (CEE), medroxyprogesterone acetate (MPA), combined CEE/MPA, or tamoxifen (TAM). Treatment with CEE/MPA down-regulated ERalpha in the superficial glands. In the superficial stroma the ERalpha level was lower in the CEE/MPA group than in the CEE and MPA groups. ERbeta immunostaining was faint with minor variation in response to treatment, but increased in the superficial stroma after MPA treatment. The ratio of ERbeta/ERalpha increased in superficial stroma and gland after CEE/MPA treatment, and also in stroma after MPA and TAM. Cystic endometrial hyperplasia was observed in TAM-treated animals, in combination with a high level of ERalpha protein expression. The present data show that long-term hormone treatment affects the ERalpha and ERbeta protein levels in the endometrium. The balance between ERalpha and ERbeta seems to be important for the proliferative response to oestrogen.

scholarly journals Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes

2012 ◽  
Vol 28 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Justine Bacchetta ◽  
Jessica L Sea ◽  
Rene F Chun ◽  
Thomas S Lisse ◽  
Katherine Wesseling-Perry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Human Monocytes ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

scholarly journals FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

2015 ◽  
Vol 226 (3) ◽  
pp. 155-166 ◽  
Author(s):  
Ichiro Kaneko ◽  
Rimpi K Saini ◽  
Kristin P Griffin ◽  
G Kerr Whitfield ◽  
Mark R Haussler ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Fibroblast Growth Factor 23 ◽  
K562 Cells ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Surface Acting ◽  
Reporter Construct ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
High Calcium

In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor 23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression and induces C/EBPβ, but does not affect leptin receptor transcription. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a fourfold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate vitamin D receptor (VDR)/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1–VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1 kb mouse FGF23 promoter–reporter construct, transfected into MC3T3-E1 osteoblast-like cells, responds to a high calcium challenge with a statistically significant 1.7- to 2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

Disorders of phosphate metabolism

2019 ◽  
Vol 72 (11) ◽  
pp. 741-747 ◽  
Author(s):  
Jenny Leung ◽  
Martin Crook
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
The Body ◽  
Plasma Phosphate ◽  
Phosphate Homeostasis ◽  
Organic Form ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Renal Tubular Reabsorption ◽  
Renal Tubular ◽  
Storage Pools

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

scholarly journals The Receptor-Dependent Actions of 1,25-Dihydroxyvitamin D Are Required for Normal Growth Plate Maturation in NPt2a Knockout Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4607-4612 ◽  
Author(s):  
Susanne U. Miedlich ◽  
Eric D. Zhu ◽  
Yves Sabbagh ◽  
Marie B. Demay
Keyword(s):  
Vitamin D ◽  
Growth Plate ◽  
Fibroblast Growth Factor 23 ◽  
Normal Growth ◽  
Chondrocyte Apoptosis ◽  
Apoptotic Pathway ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Hypertrophic Chondrocyte

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.

Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Nurul Nadirah Razali ◽  
Ting Tzer Hwu ◽  
Karuppiah Thilakavathy
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Genetic Mutations ◽  
Renal Tubules ◽  
Phosphate Homeostasis ◽  
Tooth Structure ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

AbstractHypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (

scholarly journals Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 470-481 ◽  
Author(s):  
James C. Fleet ◽  
Rebecca A. Replogle ◽  
Perla Reyes-Fernandez ◽  
Libo Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Recombinant Inbred ◽  
Inbred Mice ◽  
Recombinant Inbred Lines ◽  
Fibroblast Growth Factor 23 ◽  
Inbred Lines ◽  
Narrow Sense Heritability ◽  
Natural Genetic Variation ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Basal Serum

Abstract 1,25-Dihydroxyvitamin D (1,25[OH]2D) regulates calcium (Ca), phosphate, and bone metabolism. Serum 1,25(OH)2D levels are reduced by low vitamin D status and high fibroblast growth factor 23 (FGF23) levels and increased by low Ca intake and high PTH levels. Natural genetic variation controls serum 25-hydroxyvitamin D (25[OH]D) levels, but it is unclear how it controls serum 1,25(OH)2D or the response of serum 1,25(OH)2D levels to dietary Ca restriction (RCR). Male mice from 11 inbred lines and from 51 BXD recombinant inbred lines were fed diets with either 0.5% (basal) or 0.25% Ca from 4 to 12 weeks of age (n = 8 per line per diet). Significant variation among the lines was found in basal serum 1,25(OH)2D and in the RCR as well as basal serum 25(OH)D and FGF23 levels. 1,25(OH)2D was not correlated to 25(OH)D but was negatively correlated to FGF23 (r = −0.5). Narrow sense heritability of 1,25(OH)2D was 0.67 on the 0.5% Ca diet, 0.66 on the 0.25% Ca diet, and 0.59 for the RCR, indicating a strong genetic control of serum 1,25(OH)2D. Genetic mapping revealed many loci controlling 1,25(OH)2D (seven loci) and the RCR (three loci) as well as 25(OH)D (four loci) and FGF23 (two loci); a locus on chromosome 18 controlled both 1,25(OH)2D and FGF23. Candidate genes underlying loci include the following: Ets1 (1,25[OH]2D), Elac1 (FGF23 and 1,25[OH]2D), Tbc1d15 (RCR), Plekha8 and Lyplal1 (25[OH]D), and Trim35 (FGF23). This report is the first to reveal that serum 1,25(OH)2D levels are controlled by multiple genetic factors and that some of these genetic loci interact with the dietary environment.

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