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Calcitriol Receptor

The Experts below are selected from a list of 105 Experts worldwide ranked by ideXlab platform

Sanjeevkumar R Patel – 1st expert on this subject based on the ideXlab platform

  • effect of glucose on the function of the Calcitriol Receptor and vitamin d metabolism
    Kidney International, 1997
    Co-Authors: Sanjeevkumar R Patel, Yin Xu, Ronald J Koenig

    Abstract:

    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 α , 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.

  • Hormones – Cytokines – SignalingEffect of glyoxylate on the function of the Calcitriol Receptor and vitamin D metabolism
    Kidney International, 1997
    Co-Authors: Sanjeevkumar R Patel, Yin Xu, Ronald J Koenig

    Abstract:

    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.

  • effect of schiff base formation on the function of the Calcitriol Receptor
    Kidney International, 1996
    Co-Authors: Sanjeevkumar R Patel, Ronald J Koenig

    Abstract:

    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.

Raymond Vanholder – 2nd expert on this subject based on the ideXlab platform

  • inhibition of Calcitriol Receptor binding to vitamin d response elements by uremic toxins
    Journal of Clinical Investigation, 1995
    Co-Authors: Sanjeevkumar R Patel, Raymond Vanholder, Hui Qiong Ke, Ronald J Koenig

    Abstract:

    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.

  • The biological action of Calcitriol in renal failure
    Kidney International, 1994
    Co-Authors: Sanjeevkumar R Patel, Eric W. Young, Raymond Vanholder

    Abstract:

    Abnormal Calcitriol [1,25(OH) 2 vitamin D] metabolism plays a major role in the pathophysiology of renal osteodystrophy and other alterations of mineral metabolism associated with chronic renal failure. Growing knowledge of the protean biologic actions of Calcitriol suggests that abnormal Calcitriol metabolism may also play a role in other homeostatic perturbations associated with renal failure such as abnormal immune function [1–5], impaired growth and development [6], and abnormal cardiac [7] and skeletal muscle [8,9] function. In view of the central and enlarging role of Calcitriol in the pathophysiology of the uremic syndrome, it is important to understand the nature of altered Calcitriol metabolism in renal failure. Emerging evidence has focused on three primary areas of altered Calcitriol metabolism in renal failure: diminished production of Calcitriol, decreased concentration of the Calcitriol Receptor, and altered DNA binding properties of the Receptor-hormone complex. These alterations result in attenuated end-organ responsiveness to Calcitriol and the consequent abnormalities of mineral metabolism and other functions [10–14]. The nature of the alterations in Calcitriol metabolism are reviewed in detail in this report with an emphasis on the recently appreciated contributory role of uremic toxins.

  • inhibition of nuclear uptake of Calcitriol Receptor by uremic ultrafiltrate
    Kidney International, 1994
    Co-Authors: Sanjeevkumar R Patel, Hui Qiong Ke, Raymond Vanholder

    Abstract:

    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 3 H-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.

Hui Qiong Ke – 3rd expert on this subject based on the ideXlab platform

  • inhibition of Calcitriol Receptor binding to vitamin d response elements by uremic toxins
    Journal of Clinical Investigation, 1995
    Co-Authors: Sanjeevkumar R Patel, Raymond Vanholder, Hui Qiong Ke, Ronald J Koenig

    Abstract:

    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.

  • inhibition of nuclear uptake of Calcitriol Receptor by uremic ultrafiltrate
    Kidney International, 1994
    Co-Authors: Sanjeevkumar R Patel, Hui Qiong Ke, Raymond Vanholder

    Abstract:

    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 3 H-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.

  • regulation of Calcitriol Receptor and its mrna in normal and renal failure rats
    Kidney International, 1994
    Co-Authors: Sanjeevkumar R Patel, Hui Qiong Ke

    Abstract:

    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.