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Results for “Receptors, Calcitriol”

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At least 19 recordsLinked to original sources
PubMed1992

Serum vitamin D metabolites and calcitriol receptor concentration in parathyroid tissue in primary hyperparathyroidism.

Vitamin D metabolites in serum and calcitriol receptor concentration in parathyroid tissue were examined in 52 patients operated on for primary hyperparathyroidism. The calcitriol receptor levels were not different in parathyroid adenomas (mean 224 fmol/mg of protein, range 29-509, N = 43), normal parathyroid tissue (mean 245, range 31-690, N = 20), and primary parathyroid hyperplasia (mean 172, range 46-477, N = 9). Preoperative serum levels of calcitriol concentration correlated inversely to the calcitriol receptor in normal parathyroid tissue in patients with adenoma (r = -0.57, N = 17, p = 0.017), but no such correlation was found in the corresponding adenomas (r = 0.14, p = 0.59). In 31 patients in whom both pre- and postoperative vitamin D metabolite analyses were carried out, 23 had lower calcitriol postoperative concentrations compared to preoperative values (p = 0.012, sign test). No change was found in the other vitamin D metabolites postoperatively. By multiple regression analysis calcitriol concentration in serum was inversely correlated to the serum concentration of urea and phosphate (p = 0.003). We conclude that calcitriol may influence calcitriol receptor expression in normal parathyroid tissue, but not in adenomatous parathyroid gland. Furthermore, serum calcitriol was correlated to the renal function, and phosphate level, and in most patients the calcitriol concentration was lower after the operation.

Adenoma↗
PubMed1995

Altered vitamin D metabolism and receptor interaction with the target genes in renal failure: calcitriol receptor interaction with its target gene in renal failure.

The genomic action of calcitriol is mediated through the interaction of the calcitriol receptor (VDR) with the vitamin D response elements of the target genes. Although decreased VDR concentration in renal failure could diminish the biological action of calcitriol, recent study indicates that uremic toxins could modify the VDR DNA-binding domain and inhibit the binding of the VDR to the vitamin D response elements. The latter reaction could also account for end-organ resistance in renal failure. The inhibitory action of uremic toxins has been tested in vivo by a method using gene transcription. It was demonstrated that uremic ultrafiltrate blocks calcitriol-induced chloramphenical acetyltransferase reporter constructs containing a synthetic vitamin D response element in JEG-3 cells. Taken together, the findings indicate that uremia could underlie the calcitriol resistance in renal failure. The modification of the VDR may involve Schiff base formation between lysine residues of the VDR DNA-binding domain and reactive aldehydes accumulated in uremia. This suggestion is on the basis of the finding that the VDR and other steroid receptors form Schiff bases with pyridoxal 5'-phosphate and weaken the binding of these receptors to the DNA cellulose.

Animals↗
PubMed1996

Effect of Schiff base formation on the function of the calcitriol receptor.

The genomic action of calcitriol is mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs) of the target genes. We have shown that the interaction of VDRs with VDREs is inhibited by uremic toxins. We hypothesize that uremic toxins form Schiff bases with the lysine residues of the VDR DNA binding domain and inhibit the VDR interaction with the VDRE. In this study, pyridoxal 5'-phosphate was used as a probe to test Schiff base formation as the inhibitory mechanism, since it forms Schiff bases with steroid receptors. Pyridoxal 5'-phosphate inhibited the VDR binding to the VDREs and chemically modified the DNA binding domain of the VDR in vitro. The inhibition was reversed when pyridoxal 5'-phosphate was preincubated with lysine. Further, this chemical agent also blocked the production of chloramphenicol acetyltransferase (CAT) enzyme induced by calcitriol in cells transfected with a constructed VDRE attached to a CAT reporter gene. This finding is consistent with the hypothesis that pyridoxal 5'-phosphate could interact with the VDR and impair its DNA binding within cells. Since induction of 24-hydroxylase synthesis is a receptor mediated process, we studied the effect of pyridoxal 5'-phosphate on the synthesis of renal 24-hydroxylase in rats. When pyridoxal 5'-phosphate was infused to rats, renal 24-hydroxylase activity was suppressed, consequently, degradation of calcitriol was also reduced in these animals. Thus, chemicals capable of Schiff base formation potentially could alter the physiological function of VDR and calcitriol.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1995

Immunolocalization of calcitriol receptor, plasma membrane calcium pump and calbindin-D28k in the cornea and ciliary body of the rat eye.

Epitopes of the calcitriol receptor, the ATP-dependent plasma membrane calcium pump (PMCA) and the 28-kD vitamin-D-dependent Ca-binding protein (calbindin-D28k) were detected in sections of the albino rat eye using light microscopy and immunohistochemistry of paraffin-embedded tissues. Calcitriol receptor and calbindin-D28k epitopes were detected in both the inner and outer layers of the ciliary body epithelium. PMCA was present in both epithelial cell layers of the ciliary body but was most prominent in the inner layer. Corneal epithelium and endothelium also contained epitopes for calcitriol receptor, PMCA and calbindin-D28k. These Ca-regulatory proteins may play a role in the cellular physiology of the albino rat eye by maintaining appropriate intracellular and aqueous humor Ca concentrations.

Animals↗
PubMed1996

Developmental expression of calcitriol receptors, 9-kilodalton calcium-binding protein, and calcidiol 24-hydroxylase in human intestine.

Human intestinal mucosa consists of highly active epithelial cells in continual renewal and differentiation processes located at different portions of the villi. The crypt contains abundant replicating cells which, upon reaching the villus tip, acquire their fully differentiated state. Besides its well recognized role in bone cell homeostasis, calcitriol has been attributed a role in cellular differentiation and proliferation in normal leukocytes and myeloid leukemia cells. We have previously documented the presence and the distribution of specific calcitriol receptors in the cells of the small and large intestine from 13-20-wk-old human fetuses and that calcitriol was able to promote human intestinal epithelium proliferation or differentiation, in organ culture, depending upon fetal age. We now show that, whereas transcripts for calcitriol receptors are abundant from duodenum to colon, those for the 9-kD calcium-binding protein are present mainly in the duodenum and the jejunum and to a lesser extent in the ileum and the colon. Transcripts for 25-hydroxycholecalciferol-24-hydroxylase could not be detected in any of the intestine segments despite a prolonged exposition of the gels. Immunofluorescence staining for the 9-kD calcium-binding protein was exclusively observed in the epithelial cells of the small intestine and colon, the subepithelial layers being always negative. The 9-kD calcium-binding protein distribution along the crypt-villus axis appeared as a gradient, increasing from the developing crypt to the tip of the villus in the duodenum, jejunum, and ileum. Based on the present observations and on the fact that calcitriol promotes human fetal proliferation and differentiation, the presence of transcripts for calcitriol receptors and 9-kD calcium-binding protein in the intestinal cell opens interesting possibilities as of their role in the in utero human gut development and the control of colorectal cancers.

Calcium-Binding Proteins↗
PubMed1994

Regulation of calcitriol receptor and its mRNA in normal and renal failure rats.

Homologous up-regulation of calcitriol receptor (VDR) by calcitriol is believed to be a transcriptional event. In this experiment, we studied the effect of calcitriol on VDR in normal and renal failure rats. The time course of the effect of calcitriol on VDR mRNA showed a biphasic change in VDR mRNA in response to calcitriol. The concentration of intestinal VDR mRNA increased at six hours and reached peak levels approximately 15 hours after calcitriol injection. Thereafter, the mRNA began to decrease and by 48 hours the level had declined to below the control values. The VDR levels also increased, though they lagged behind the VDR mRNA, and nearly plateaued at 24 hours after calcitriol treatment. In renal failure, the concentrations of VDR were lower and the levels of VDR mRNA were higher than the respective values of normal rats, suggesting that VDR synthesis was inhibited at post-transcriptional sites. Chronic administration of calcitriol increased the VDR but lowered the VDR mRNA levels in both normal and renal failure rats. Infusion of uremic ultrafiltrate to normal rats resulted in lower VDR and higher VDR mRNA levels similar to those found in rats with renal failure. The results indicate that uremic toxins are responsible for the low VDR and high VDR mRNA in renal failure.

Animals↗
PubMed1990

Studies of the porcine intestinal calcitriol receptor in pseudo-vitamin D deficiency rickets type I.

1. Calcitriol (1,25-dihydroxyvitamin D3) concentrations in plasma of humans and pigs with pseudo-vitamin D deficiency rickets type I (PVDRI) have been reported to be significantly lower than in normal subjects and animals. Sometimes, however, calcitriol concentrations are relatively high in these subjects and animals (50-80 pmol/l) and nevertheless clinical symptoms of rickets develop. We have studied whether or not the development of rachitic lesions in piglets with PVDRI is due to altered binding properties of the intestinal calcitriol receptor in addition to the defective renal production of calcitriol. PVDRI piglets with clinical and biochemical symptoms of rickets (hypocalcaemia, increased activity of alkaline phosphatase) and with calcitriol concentrations in plasma of 83.7 +/- 4.2 pmol/l (n = 7) were used. They were compared with unaffected piglets with normal calcitriol concentrations (178.0 +/- 17.7 pmol/l, n = 9). 2. The equilibrium dissociation constant (Kd) of the receptor in the PVDRI piglets (0.31 +/- 0.05 nmol/l) and in control piglets (0.33 +/- 0.05 nmol/l) and the maximum binding capacity (Bmax.) (674 +/- 103 and 719 +/- 122 fmol/mg of protein, respectively) were not different (n = 9). 3. The association rate constant (kass) at 4 degrees C [0.15 x 10(7) and 0.24 x 10(7) (mol/l)-1 min-1] and the dissociation rate constant (kdiss) (0.40 x 10(-3) and 0.48 x 10(-3) min-1; half-life of dissociation = 24.1 and 28.9 h, respectively) were also not different between diseased and control piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1997

Effect of glyoxylate on the function of the calcitriol receptor and vitamin D metabolism.

The biological action of calcitriol is mostly mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs) of target genes. These interactions produce special proteins that carry out the biological activities of calcitriol. Recently, we showed that the interaction of VDRs with VDREs is inhibited by uremic toxins. We hypothesize that uremic toxins that contain aldehyde or ketone groups potentially could form Schiff bases with lysine residues of the VDR DNA binding domain and inhibit VDR interaction with VDREs. We therefore chose glyoxylate, a compound which has an aldehyde group, to test this hypothesis. In vitro glyoxylate inhibited VDR binding to the osteocalcin and osteopontin VDREs as assessed by electrophoretic mobility shift assay and the inhibition was reversed when glyoxylate was preincubated with lysine. Further, this chemical compound also blocked the induction of chloramphenicol acetyltransferase (CAT) enzyme induced by calcitriol in cells transfected with a calcitriol responsive CAT reporter gene. Since induction of 24-hydroxylase synthesis is a VDR regulated process, we also studied the effect of glyoxylate on the activity of intestinal 24-hydroxylase in rats. This enzyme activity was suppressed in rats infused with glyoxylate. Taken together, our study suggests that glyoxylate could inhibit the interaction of VDR with VDREs and alter the biological action of calcitriol.

Animals↗
PubMed1993

Mechanism of decreased intestinal calcitriol receptor concentration in renal failure.

The biological actions of calcitriol and its receptor synthesis are believed to be mediated through the calcitriol-receptor complex interacting with nuclear chromatin of target cells. Thus inhibition of the receptor interaction with DNA could diminish the biological actions of calcitriol and upregulation of its receptor. We found that uremic ultrafiltrate reduced the receptor interaction with DNA in vitro. DNA-cellulose chromatography showed that the receptor from normal rats and rats infused with normal ultrafiltrate eluted as a single peak at 0.22 M KCl, whereas chronic renal failure rats and rats infused with uremic ultrafiltrate had two receptor peaks, i.e., one of normal activity at 0.22 M KCl and the other of weak activity at 0.12 M KCl. Furthermore, infusion of uremic ultrafiltrate to normal rats reduced the intestinal calcitriol receptor concentration (397 +/- 15.8 vs. 307 +/- 15.4 fmol/mg protein, both n = 4, P < 0.005). Uremic ultrafiltrate also suppressed the calcitriol-induced upregulation of the receptor (816 +/- 34.6 vs. 606 +/- 35.3 fmol/mg protein, P < 0.005). It appears that uremic toxins may reduce the biological action of calcitriol in renal failure by inhibiting receptor synthesis and the interaction of the hormone-receptor complex with nuclear chromatin.

Animals↗
PubMed1997

Effect of glucose on the function of the calcitriol receptor and vitamin D metabolism.

The genomic action of calcitriol is mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs) of the target genes. It has been proposed that chemicals capable of Schiff base formation with the VDR potentially could alter the physiological function of VDR and calcitriol metabolism. Since glucose has been shown to form Schiff bases with proteins, we tested the hypothesis that glucose could influence the function of VDR and thereby alter calcitriol metabolism. Glucose 6-phosphate inhibited VDR binding to the osteocalcin VDRE and chemically modified the DNA binding domain or the dimerization domain of the VDR in vitro. Further, glucose also blocked the production of chloramphenicol acetyltransferase (CAT) enzyme induced by calcitriol in cells transfected with a constructed VDRE attached to a CAT reporter gene. Hyperglycemia induced by glucose infusion or by streptozotocin in normal rats significantly reduced intestinal 1 alpha, 25-dihydroxyvitamin D-24-hydroxylase activity. Taken together, these findings are consistent with the hypothesis that glucose could interact with the VDR to impair its DNA binding and function within cells.

Animals↗
PubMed1990

Cultured osteoblasts from normal and hypophosphatemic mice: calcitriol receptors and biological response to the hormone.

The content and affinity of calcitriol receptors were analyzed in cultured osteoblasts from normal and hypophosphatemic mice. Hypertonic cell extracts were prepared by sonication followed by centrifugation at 200,000 g x 30 min. Analysis, at saturating levels of labeled 1,25(OH)2D3, revealed that binding of the hormone was dependent on the density of the cells plated and on the length of time in culture. It reached a maximum at 5 days of culture when 1.0 x 10(6) cells were plated. Under those conditions the binding capacity of Hyp osteoblasts was 6306 +/- 1267 sites/ng protein (mean +/- SEM) not different from N cells (7594 +/- 1713). The dissociation constant (Kd) was 18.3 +/- 5.4 and 20.0 +/- 5.7 pM for mutant and normal mouse osteoblasts respectively (NS). In both genotypes, a single peak for specific binding, migrating at approximately 3.0-3.5 S was observed by sucrose gradient centrifugation. 25-hydroxycholecalciferol-24-hydroxylase (24-OHase) was induced at 1 and 10 nM 1,25(OH)2D3 in a dose-dependent fashion. However, the induction was higher in mutant than in normal cells when the medium contained 1 mM and 2 mM phosphate salts. The difference vanished when cells were incubated in the presence of 3 and 4 mM phosphate salts. The effect of calcitriol on cultured osteoblasts was also analyzed in terms of collagen synthesis and alkaline phosphatase activity. In the range of 10(-10) M to 10(-7) M, 1,25(OH)2D3 was found to inhibit collagen synthesis in a dose-dependent fashion. At physiological levels, 1,25(OH)2D3 (10(-11)M-10(-10)M), stimulated alkaline phosphatase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1995

Immuno-localization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye.

Using immunohistochemical methods, we detected epitopes of the calcitriol receptor, the ATP-dependent plasma membrane calcium pump and the 28kD vitamin D-dependent calcium-binding protein in sections of the human eye. In retinal photoreceptors, vitamin D receptor, plasma membrane calcium pump and calcium-binding protein epitopes were detected in the outer nuclear layer. Epitopes for the vitamin D receptor and the calcium-binding protein were present in the inner and outer segments of the photoreceptors, where visual transduction occurs. All three proteins were detected in some cells of the ganglion cell layer, the inner nuclear layer, and the retinal pigment epithelium. Epitopes for these proteins also were noted in the ciliary body epithelium. VDR epitopes were seen in lens epithelium. Some immunostaining for VDR, PMCA and calbindin-D28k also was present in the endothelium and in the basal epithelium of the cornea. The presence of these proteins in several tissues of the human eye suggests that the proteins may play a role in the cellular physiology of the eye. Their exact functions in the eye remain undetermined.

Antibodies, Monoclonal↗
PubMed1995

Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins.

The genomic action of calcitriol (1,25-dihydroxy-vitamin D3) is mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs). Although renal failure is associated with resistance to the action of calcitriol, the mechanism of this resistance is not well understood. Therefore, we used the electrophoretic mobility shift assay to compare the ability of VDRs from normal and renal failure rats to bind to the osteocalcin gene VDRE. The results indicate that VDRs from renal failure rats have only half the DNA binding capacity as VDRs from control rats, despite identical calcitriol binding. Furthermore, incubation of normal VDRs with a uremic plasma ultrafiltrate resulted in a loss of > 50% of the binding sites for the osteocalcin VDRE. When VDRs bound to DNA as heterodimers with retinoid X receptors, the inhibitory effect of the uremic ultrafiltrate was due to a specific interaction with the VDR, not retinoid X receptors. In addition, uremic ultrafiltrate blocked calcitriol-induced reporter gene activity in transfected JEG-3 cells. Taken together, the results indicate that an inhibitory effect of a uremic toxin(s) on VDR-VDRE binding could underlie the calcitriol resistance of renal failure.

Animals↗
PubMed1994

Inhibition of nuclear uptake of calcitriol receptor by uremic ultrafiltrate.

The biological action of calcitriol is mediated through a hormone-receptor complex interacting with nuclear chromatin. Interaction of the calcitriol receptor (VDR) with VDR response elements produces bioactive proteins which carry out the physiological actions of calcitriol. Since biological response to calcitriol appears to be diminished in renal failure, we studied the effect of uremic toxins on the interaction of VDR with nuclear chromatin using in vitro nuclear uptake of the 3H-calcitriol labeled VDR by intestinal nuclei. We found that nuclear uptake of the labeled intestinal VDR from renal failure rats was significantly lower than that from the control animals. HPLC fractionated uremic ultrafiltrate directly inhibited nuclear uptake of the labeled VDR when the labeled VDR was incubated with 50% of the ultrafiltrate for various time intervals ranging from 15 minutes to 6 hours. Infusion of uremic ultrafiltrate to normal rats for 20 hours also produced intestinal VDR with a lower binding affinity for intestinal nuclei when compared to the controls infused with normal ultrafiltrate. The latter study suggests that uremic toxins are responsible for the decreased nuclear uptake of VDR of rats with renal failure. Although it is difficult to extrapolate these results directly to the intact cells, our findings suggest that part of the calcitriol resistance in renal failure could be explained by decreased entry of receptor into the nucleus.

Animals↗
PubMed1990

Presence and binding characteristics of calcitriol receptors in human fetal gut.

In the present study, we show for the first time the presence of calcitriol-specific binding sites in hypertonic extracts of cells isolated from human fetal small intestine and colon from 13-21 weeks of gestation. Woolf plot analysis of the binding characteristics revealed the presence of a single class of high affinity receptors. The presence of specific receptors for calcitriol in fetal intestine and colon opens interesting possibilities as to the role of this hormone in human gut development.

Calcitriol↗
PubMed1994

Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney.

The precise localization of the calcitriol (1 alpha,25-dihydroxyvitamin D3) receptor (VDR) and the 25-hydroxyvitamin D3 [25(OH)D3] 24-hydroxylase cytochrome P-450 in the human kidney is unknown. Using newly developed polyclonal antibodies against the human VDR, we demonstrate that the receptor is present in cells of the distal tubule, the collecting duct, the proximal tubule, and in the parietal epithelial cells of the glomerulus. In the distal tubule and collecting duct not all cells contain epitopes for the receptor. The protein is not detected in glomerular capillaries, in the glomerular mesangium, in the interstitium, or in blood vessels. Specific polyclonal antibodies directed against the 25(OH)D3 24-hydroxylase cytochrome P-450 demonstrate epitopes for the cytochrome in cells of the proximal tubule, the distal tubule, glomerular parietal epithelial cells, and mesangial cells. The protein is absent from interstitial cells. Calbindin D28k is present exclusively in principal cells of the distal tubule and collecting duct. In the human kidney, the VDR is present in cells where vitamin D-inducible proteins are found; conversely it is absent from cells where vitamin D-dependent proteins are not present.

Animals↗
PubMed1991

Calcitriol receptors in rat thyroid follicular cells (FRTL-5).

The FRTL-5 cell line is widely used as a model for normal thyroid follicular cells. These cells have retained their ability to alter cAMP production, cell proliferation, iodine uptake, and thyroglobulin synthesis in response to thyrotropin. We have previously shown that calcitriol attenuated both basal and TSH stimulated cAMP production dose-dependently in FRTL-5 cells. Cytosol fractions (105,000 g, 60 min, 4 degrees C) prepared from FRTL-5 cell homogenates possessed calcitriol-binding components with a sedimentation coefficient of approximately 3.7 S in high salt (0.3 mol/l KCl) sucrose gradients (5-20%). At 4 degrees C, specific binding increased rapidly during the first 4 h and reached a plateau after 8 h. The specific binding (18 h, 4 degrees C) was maximal at a [3H]calcitriol concentration of approximately 0.5 nmol/l. Scatchard analysis of the binding data indicated one single class of high affinity binding sites with Kd = 105 +/- 2 pmol/l and Bmax = 38.5 +/- 4.7 pmol/g cytosol protein (mean +/- SD, N = 6). In conclusion, our results suggest that the FRTL-5 cells possess functional receptors for calcitriol with the same physicochemical properties as the receptors found in normal rat tissues.

Animals↗