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Details for receptor: VDR

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EndoNet ID: ENR00664

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Synonyms

  • VDR
  • 1,25-dihydroxyvitamin D3 receptor
  • vitamin D receptor
  • 1alpha,25-dihydroxy Vitamin D3 receptor
  • calcitriol receptor
  • NR1I1

General information

  • VDR mRNA could be amplified and demonstrated in a human kidney proximal tubule cell line, CL-8. [1]
  • We have shown clear amplification of VDR transcripts within sections of formalin-fixed paraffin-embedded human kidney and liver. [1]
  • Hepatocytes express very low VDR(n) messenger RNA (mRNA) and protein levels. [2]
  • member of the nuclear receptor family of transcription factors

Links to other resources

UniProt P11473
Ensembl ENST00000395324

Binding hormones

  • calcitriol
    • The effects of 1alpha,25- (OH)2D3 are primarily mediated by its nuclear receptor (the vitamin D receptor or VDR). [3]

Anatomical structures with this receptor

  • kidney

    Influences

    • negative calcitriol
      • The synthesis of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is most strongly regulated by dietary calcium and the action of parathyroid hormone to increase 1α-hydroxylase (1α-OHase) and decrease 24-hydroxylase (24-OHase) in kidney proximal tubules. [4]
      • 1,25-(OH)2D3 synthesis, induced by dietary calcium restriction, is also the result of negative feedback regulation blockade. [5]
      • Tissue-specific down-regulation of VDR by hypocalcemia blocks the 1,25-(OH)2D3 suppression of the 1α-OHase and upregulation of the 24-OHase in the kidney, causing a marked accumulation of 1,25-(OH)2D3 in the plasma. [5]
      • VDR clearly mediates the induction of the 24-OHase and the suppression of the 1α-OHase by 1,25-(OH)2D3. [6]
      • Thus, the PTH secreted under hypocalcemic conditions causes unbridled 1α-OHase activity in kidney and completely suppresses the 24-OHase activity causing high levels of 1,25-(OH)2D3 in the circulation. [7]
      • The accumulation of 1,25-(OH)2D3 in the plasma is because of high rates of production and an absence of renal degradation. This impressive regulation only serves to ensure high rates of calcium mobilization from bone as needed for soft tissue needs such as growth as shown by bone ash and skeletal density determinations. [5]
      • Loss of renal VDR interferes with the otherwise normal ability of 1,25-(OH)2D3 to exert negative feedback suppression on 1α-OHase. It, therefore, appears that the basis of this regulatory series of events rests with the regulation of VDR expression in renal and perhaps parathyroid cells by ambient calcium concentrations. [5]

    Induced phenotypes

    • phosphate ion homeostasis
      • The homeostasis of serum Pi levels is effected through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. [8]
      • These processes are primarily regulated by 1-alpha,25-dihydroxyvitamin D [1,25(OH)2D3]. [9]
    • Secondary hyperparathyroidism
      • Chronic renal failure is the most common cause of secondary hyperparathyroidism. Failing kidneys do not convert enough vitamin D to its active form, and they do not adequately excrete phosphorus. [10]

  • osteoblast

    Influences

    • positive TGF-beta 2
    • positive RANKL
    • positive FGF-23
      • The bone, likely the osteoblast or its precursor cell, is a major source of FGF23 in response to 1alpha,25-Dihydroxyvitamin D3. [11]
      • This establishes a reciprocal relationship between 1,25(OH)2D3 and FGF23, with phosphatemic 1,25(OH)2D3 hormone generated in the kidney, inducing skeletal endocrine cells to produce FGF23, which then feedback represses renal 1alpha-OHase to curtail 1,25(OH)2D3 biosynthesis as well as inhibits the renal reabsorption of phosphate to elicit phosphaturia. [11]
      • 1,25(OH)2D3-induced FGF23 from bone constitutes the final link in a renal-gastrointestinal-skeletal axis that controls serum phosphate and active vitamin D levels. [11]

    Induced phenotypes

    • regulation of gene expression
      • After binding of calcitriol vitamin D receptor regulates gene transcription by binding to vitamin D responsive elements in promotor region of target genes. [12]
    • alopecia
      • Functional inactivation of vitamin D receptor results in alopecia. [12]
    • mineral metabolism
      • Calcitriol, the biologically active form of vitamin D, is essential for intact mineral metabolism,has important roles in calcium and phosphate homeostasis and in the regulation of cell proliferation and differentiation. [13]
    • rickets
      • Functional inactivation of vitamin D receptor results in rickets. [12]

  • chief_cell_of_parathyroid_gland

    Influences

    • negative PTH
      • Binding of extracellular calcium to the CaSR makes it possible to suppress the secretion of parathyroide hormone (PTH) from the parathyroid glands in patients with overactivity of these glands. [14]

  • hematopoietic_stem_cell

    Influences

    • positive RANKL

  • hepatocyte

    Induced phenotypes

    • negative regulation of bile acid biosynthetic process
      • Lithocholic acid acetate or 1α, 25-dihydroxy-vitamin D3-activated VDR strongly inhibites cholesterol 7α-hydroxylase mRNA expression and reduces bile acid synthesis in human hepatocytes. [15]
    • VDR protein and mRNA were identified in primary human hepatocytes. [15]

  • beta_cell_of_islet_of_Langerhans

    Influences

    • positive insulin
      • Insulin but not glucagon release is reduced after stimulation with glucose and arginine in isolated perfused pancreas from vitamin D-deficient rats. [16]
      • Glucose tolerance and insulin secretion are impaired in vitamin D-deficient rats in vivo. [17]
      • nonfunctioning VDR is assiciated with impaired glucose tolerance and reduced maximum insulin secretory capacity, independent of changes in calcium homeostasis. [18]

  • bone

    Influences

    • positive FGF-23
      • The bone, likely the osteoblast or its precursor cell, is a major source of FGF23 in response to 1alpha,25-Dihydroxyvitamin D3. [11]
      • This establishes a reciprocal relationship between 1,25(OH)2D3 and FGF23, with phosphatemic 1,25(OH)2D3 hormone generated in the kidney, inducing skeletal endocrine cells to produce FGF23, which then feedback represses renal 1alpha-OHase to curtail 1,25(OH)2D3 biosynthesis as well as inhibits the renal reabsorption of phosphate to elicit phosphaturia. [11]
      • 1,25(OH)2D3-induced FGF23 from bone constitutes the final link in a renal-gastrointestinal-skeletal axis that controls serum phosphate and active vitamin D levels. [11]

    Induced phenotypes

    • tumor-induced osteomalacia
      • Ectopic overproduction of FGF23 overwhelms its processing and degradation, leading to TIO. [19]
      • Administration of recombinant FGF23 in normal and parathyroidectomized animals induced a decrease in serum phosphate levels, phosphaturia accompanied by a reduction in renal mRNA and protein levels for sodium-phosphate cotransport activites in the kidney, a decrease in renal mRNA for 25-hydroxyvitamin D-1{alpha}-hydroxylase, and an increase in 25-hydroxyvitamin D-24-hydroxylase, the cytochrome P-450 enzymes that generate and inactivate 1,25(OH)2D3 hormone, respectively [19]
      • Mice implanted with FGF23-expressing Chinese hamster ovary (CHO) cells showed more severe hypophosphatemia, osteomalacia, and decreased 1,25(OH)2D3 levels. [19]
    • autosomal dominant hypophosphatemic rickets
      • Missense mutations in FGF23, which likely prevent its cleavage and inactivation, are the cause of ADHR. [20]
      • Administration of an ADHR mutant form of FGF23 to mice inhibited sodium-phosphate cotransport activities in both the kidney and small intestine, and suppressed 1,25(OH)2D3. [21]
    • X-linked hypophosphatemic rickets
      • Elevated circulating FGF23 levels have been found in most, but not all, patients with XLH. [22]
    • osteoporosis
      • The primary form of circulating vitamin D, 25-hydroxy-vitamin D, is a modifiable quantitative trait associated with multiple medical outcomes, including osteoporosis. [23]

  • macrophage

    Induced phenotypes

    • negative regulation of macrophage derived foam cell differentiation
      • Activation of vitamin D receptor signaling prevents foam cell formation by reducing modified LDL cholesterol uptake in macrophages. [24]

  • keratinocyte

    Influences

    • positive cathelicidin
      • We provide evidence that the CAMP gene is a direct target of the transcription factor vitamin D receptor (VDR) that mediates the strong up-regulation of CAMP in response to treatment of cells with vitamin D3 [25]
    • Epidermal keratinocytes not only synthesize vitamin D by a photochemical process, they also contain the vitamin D receptor. [26]
Reference