scholarly journals Importance of apical membrane delivery of 1,25-dihydroxyvitamin D3 to vitamin D-responsive gene expression in the colon

2012 ◽  
Vol 303 (7) ◽  
pp. G870-G878 ◽  
Author(s):  
Nicholas J. Koszewski ◽  
Ronald L. Horst ◽  
Jesse P. Goff
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Intestinal Tract ◽  
Apical Membrane ◽  
Dihydroxyvitamin D3 ◽  
Surgical Ligation ◽  
Dihydroxyvitamin D ◽  
Equimolar Dose ◽  
Dose Dependent Increase ◽  
Dose Dependent

Synthetic conjugation of a glucuronide to 1,25-dihydroxyvitamin D3 (1,25D3) to produce β-25-monoglucuronide-1,25D3 (βGluc-1,25D3) renders the hormone biologically inactive and resistant to mammalian digestive enzymes. However, β-glucuronidase produced by bacteria in the lower intestinal tract can cleave off the glucuronide, releasing the active hormone. In mice given a single oral dose of 1,25D3, 24-hydroxylase (Cyp24a1) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D3 that peaked at ∼3.0 nmol/l. In contrast, in mice treated with an equimolar dose of βGluc-1,25D3, Cyp24a1 gene expression increased 700-fold in the colon but was significantly weaker in the duodenum compared with mice treated with 1,25D3. Similar results were observed with another vitamin D-dependent gene. When administered subcutaneously, 1,25D3 weakly stimulated colon Cyp24a1 gene expression while βGluc-1,25D3 again resulted in strong enhancement. Surgical ligation to block passage of ingesta beyond the upper intestinal tract abolished upregulation of colon Cyp24a1 gene expression by orally and subcutaneously administered βGluc-1,25D3. Feeding βGluc-1,25D3 for 5 days revealed a linear, dose-dependent increase in colon Cyp24a1 gene expression but did not significantly increase plasma 1,25D3 or calcium concentrations. This study indicates that the colon is relatively insensitive to circulating concentrations of 1,25D3 and that the strongest gene enhancement occurs when the hormone reaches the colon via the lumen of the intestinal tract. These findings have broad implications for the use of vitamin D compounds in colon disorders and set the stage for future therapeutic studies utilizing βGluc-1,25D3 in their treatment.

Rat calcium-sensing receptor is regulated by vitamin D but not by calcium

1996 ◽  
Vol 270 (3) ◽  
pp. F454-F460 ◽  
Author(s):  
A. J. Brown ◽  
M. Zhong ◽  
J. Finch ◽  
C. Ritter ◽  
R. McCracken ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Calcium Sensing Receptor ◽  
Calcium Receptor ◽  
Dihydroxyvitamin D3 ◽  
Calcium Sensing ◽  
Wide Range ◽  
A Cell ◽  
Dose Dependent Increase ◽  
Dose Dependent

Parathyroid hormone (PTH) secretion is regulated by extracellular calcium acting through a cell surface calcium receptor (CaR). We have examined the potential regulation of the CaR in the parathyroid glands (PTG) and kidney by calcium and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Rats fed vitamin D-deficient (-D) diets containing 0.02, 0.4, or 2.0% Ca had a wide range of serum ionized Ca (2.5-5.2 mg/dl) and PTH (22-590 pg/ml) concentrations. PTG CaR mRNA did not vary significantly with ionized calcium or PTH, indicating that hypocalcemia and hyperparathyroidism may not alter CaR expression. However, PTG CaR mRNA was 40% lower in the -D rats than in age-matched rats fed a vitamin D-replete (+D) diet (P < 0.002). Repletion of -D rats with 1,25-(OH)2D3 produced a dose-dependent increase in PTG CaR mRNA. Treatment of +D rats with 100 ng of 1,25-(OH)2D3 increased CaR mRNA by 33% (P < 0.05) and 54% (P < 0.002) in the PTG and by 89% (P < 0.02) and 91% (P < 0.02) in the kidney in two independent experiments. PTG CaR peaked at 16 h (150% of control, P < 0.05) after 1,25-(OH)2D3 administration but returned to normal by 24 h. This upregulation of CaR expression by 1,25-(OH)2D3 may be involved in the suppressive effects of vitamin D compounds on PTH secretion.

scholarly journals Activation of Receptor Activator of NF-κB Ligand Gene Expression by 1,25-Dihydroxyvitamin D3 Is Mediated through Multiple Long-Range Enhancers

2006 ◽  
Vol 26 (17) ◽  
pp. 6469-6486 ◽  
Author(s):  
Sungtae Kim ◽  
Miwa Yamazaki ◽  
Lee A. Zella ◽  
Nirupama K. Shevde ◽  
J. Wesley Pike
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Chromatin Modification ◽  
Response Element ◽  
Dihydroxyvitamin D3 ◽  
Specific Element ◽  
Dihydroxyvitamin D

ABSTRACT RANKL is a tumor necrosis factor (TNF)-like factor secreted by mesenchymal cells, osteoblast derivatives, and T cells that is essential for osteoclastogenesis. In osteoblasts, RANKL expression is regulated by two major calcemic hormones, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and parathyroid hormone (PTH), as well as by several inflammatory/osteoclastogenic cytokines; the molecular mechanisms for this regulation are unclear. To identify such mechanisms, we screened a DNA microarray which tiled across the entire mouse RankL gene locus at a 50-bp resolution using chromatin immunoprecipitation (ChIP)-derived DNA precipitated with antibodies to the vitamin D receptor (VDR) and the retinoid X receptor (RXR). Five sites of dimer interaction were observed on the RankL gene centered at 16, 22, 60, 69, and 76 kb upstream of the TSS. These regions contained binding sites for not only VDR and RXR, but also the glucocorticoid receptor (GR). The most distant of these regions, termed the distal control region (RL-DCR), conferred both VDR-dependent 1,25(OH)2D3 and GR-dependent glucocorticoid (GC) responses. We mapped these activities to an unusual but functionally active vitamin D response element and to several potential GC response elements located over a more extensive region within the RL-DCR. An evolutionarily conserved region within the human RANKL gene contained a similar vitamin D response element and exhibited an equivalent behavior. Importantly, hormonal activation of the RankL gene was also associated with chromatin modification and RNA polymerase II recruitment. Our studies demonstrate that regulation of RankL gene expression by 1,25(OH)2D3 is complex and mediated by at least five distal regions, one of which contains a specific element capable of mediating direct transcriptional activation.

scholarly journals 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle

2003 ◽  
Vol 10 (6) ◽  
pp. 1129-1135 ◽  
Author(s):  
S. G. Rhodes ◽  
L. A. Terry ◽  
J. Hope ◽  
R. G. Hewinson ◽  
H. M. Vordermeier
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Proliferation ◽  
Accessory Cell ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Cell Responses ◽  
1,25 Dihydroxyvitamin D ◽  
Accessory Cells

ABSTRACT This report describes the presence and activity of 1,25-dihydroxyvitamin D3 (1,25-D3) in experimental bovine tuberculosis. Animals that went on to develop tuberculous lesions exhibited a rapid transient increase in serum 1,25-D3 within the first 2 weeks following infection with Mycobacterium bovis. 1,25-D3-positive mononuclear cells were later identified in all tuberculous granulomas by immunohistochemical staining of postmortem lymph node tissue. These results suggest a role for 1,25-D3 both at the onset of infection and in the development of the granuloma in these infected animals. Using a monoclonal antibody to the vitamin D receptor (VDR) as a VDR agonist, we confirmed that activation of the vitamin D pathway profoundly depresses antigen-specific, but not mitogenic, bovine peripheral blood T-cell responses (proliferation and gamma interferon production). Investigation of the mechanism of this suppression showed that the VDR antibody modified the expression of CD80 by accessory cells, such that a significant positive correlation between T-cell proliferation and accessory cell CD80 emerged.

Insulin modulates the stimulation of renal 1,25-dihydroxyvitamin D3 production by parathyroid hormone

1985 ◽  
Vol 109 (2) ◽  
pp. 243-248 ◽  
Author(s):  
Nirandon Wongsurawat ◽  
H. James Armbrecht
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Diabetic Rats ◽  
Biologically Active ◽  
Renal Handling ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Maximal Stimulation ◽  
Insulin Replacement ◽  
Stimulation Of

Abstract. Previous studies have shown that there is an impairment in renal production of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the major biologically active metabolite of vitamin D3, in diabetes. This impairment is not due to a deficiency in the parathyroid hormone (PTH), a major stimulator of renal 1,25(OH)2D3 production. Therefore, we have investigated the capacity of PTH to stimulate 1,25(OH)2D3 production in insulin deficiency and with insulin replacement. Experiments were performed in rats fed a 0.6% calcium, vitamin D sufficient diet for 2 weeks. Thyroparathyroidectomy was performed on all rats. Rats to be rendered diabetic were injected with streptozotocin immediately after surgery. In non-diabetic rats, PTH administration significantly increased renal 1,25(OH)2D3 production (11 ± 2 vs 46 ± 5 pg/min/g; P < 0.05). In diabetic rats, however, PTH caused only a modest increase in 1,25(OH)2D3 production (11 ± 1 vs 19 ± 4 pg/min/g; P < 0.05). With insulin replacement, PTH stimulation of 1,25(OH)2D3 production was markedly increased over that seen in diabetic rats (48 ± 12 vs 19 ± 4 pg/min/g; P < 0.05). PTH was equally effective in raising serum calcium, depressing serum phosphorus and tubular reabsorption of phosphate in non-diabetic as well as in diabetic rats. These results demonstrate that insulin is necessary for the maximal stimulation of renal 1,25(OH)2D3 production by PTH. However, insulin is not necessary for PTH action in terms of renal handling of phosphate and inducing hypercalcaemia. These results suggest multiple pathways for the action of PTH, only some of which are insulin requiring.

scholarly journals Gene expression during THP-1 differentiation is influenced by vitamin D3 and not vibrational mechanostimulation

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11773
Author(s):  
Theodoros Simakou ◽  
Robin Freeburn ◽  
Fiona L. Henriquez
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Vitamin D3 ◽  
Inflammatory Responses ◽  
Expression Patterns ◽  
Combined Treatment ◽  
Mechanical Stimulus ◽  
Suspension Cells ◽  
Macrophage Differentiation ◽  
Dihydroxyvitamin D3

Background In injury or infection, monocytes migrate into the affected tissues from circulation and differentiate into macrophages which are subsequently involved in the inflammatory responses. Macrophage differentiation and activation have been studied in response to multiple chemokines and cytokines. However, mechanical, and physical stimuli can also influence macrophage differentiation, activation, cytokine production, and phagocytic activity. Methods In this study the macrophage differentiation from THP-1 monocytes was assessed upon the stimulation with 1,25-dihydroxyvitamin D3 and 1,000 Hz vibrations, using qPCR for quantification of transcript expression. Vitamin D binds the vitamin D receptor (VDR) and subsequently modulates the expression of a variety of genes in monocytes. The effects of the 1,000 Hz vibrational stimulation, and the combined treatment of vitamin D3 and 1000 Hz vibrations were unknown. The differentiation of macrophages was assessed by looking at transcription of macrophage markers (e.g., CD14, CD36), antigen presenting molecules (e.g., HLA-DRA), transcription factors (e.g., LEF-1, TCF7L2), and mechanosensors (e.g., PIEZO1 and PKD2). Results The results showed that vitamin D3 induced THP-1 macrophage differentiation, which was characterized by upregulation of CD14 and CD36, downregulation of HLA-DRA, upregulation of the PKD2 (TRPP2), and an inverse relationship between TCF7L2 and LEF-1, which were upregulated and downregulated respectively. The 1,000 Hz vibrations were sensed from the cells which upregulated PIEZO1 and TCF3, but they did not induce expression of genes that would indicate macrophage differentiation. The mRNA transcription profile in the cells stimulated with the combined treatment was comparable to that of the cells stimulated by the vitamin only. The 1,000 Hz vibrations slightly weakened the effect of the vitamin for the regulation of CD36 and HLA-DMB in the suspension cells, but without causing changes in the regulation patterns. The only exception was the upregulation of TCF3 in the suspension cells, which was influenced by the vibrations. In the adherent cells, the vitamin D3 cancelled the upregulating effect of the 1,000 Hz vibrations and downregulated TCF3. The vitamin also cancelled the upregulation of PIEZO1 gene by the 1,000 Hz vibrations in the combined treatment. Conclusion The mechanical stimulation with 1,000 Hz vibrations resulted in upregulation of PIEZO1 in THP-1 cells, but it did not affect the differentiation process which was investigated in this study. Vitamin D3 induced THP-1 macrophage differentiation and could potentially influence M2 polarization as observed by upregulation of CD36 and downregulation of HLA-DRA. In addition, in THP-1 cells undergoing the combined stimulation, the gene expression patterns were influenced by vitamin D3, which also ablated the effect of the mechanical stimulus on PIEZO1 upregulation.

scholarly journals Analysis of 1,25-Dihydroxyvitamin D3 Genomic Action Reveals Calcium-Regulating and Calcium-Independent Effects in Mouse Intestine and Human Enteroids

2020 ◽  
Vol 41 (1) ◽  
pp. e00372-20
Author(s):  
Shanshan Li ◽  
Jessica De La Cruz ◽  
Steven Hutchens ◽  
Somshuvra Mukhopadhyay ◽  
Zachary K. Criss ◽  
...  
Keyword(s):  
Vitamin D ◽  
Calcium Transport ◽  
Target Genes ◽  
Dihydroxyvitamin D3 ◽  
Transgenic Expression ◽  
Distal Intestine ◽  
Dihydroxyvitamin D ◽  
Active Calcium ◽  
Independent Effects ◽  
Proximal Intestine

ABSTRACTAlthough vitamin D is critical for the function of the intestine, most studies have focused on the duodenum. We show that transgenic expression of the vitamin D receptor (VDR) only in the distal intestine of VDR null mice (KO/TG mice) results in the normalization of serum calcium and rescue of rickets. Although it had been suggested that calcium transport in the distal intestine involves a paracellular process, we found that the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated genes in the proximal intestine associated with active calcium transport (Trpv6, S100g, and Atp2b1) are also induced by 1,25(OH)2D3 in the distal intestine of KO/TG mice. In addition, Slc30a10, encoding a manganese efflux transporter, was one of the genes most induced by 1,25(OH)2D3 in both proximal and distal intestine. Both villus and crypt were found to express Vdr and VDR target genes. RNA sequence (RNA-seq) analysis of human enteroids indicated that the effects of 1,25(OH)2D3 observed in mice are conserved in humans. Using Slc30a10−/− mice, a loss of cortical bone and a marked decrease in S100g and Trpv6 in the intestine was observed. Our findings suggest an interrelationship between vitamin D and intestinal Mn efflux and indicate the importance of distal intestinal segments to vitamin D action.

scholarly journals Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

2020 ◽  
Vol 245 (16) ◽  
pp. 1474-1489
Author(s):  
Chandrashekar Annamalai ◽  
Rajesh N Ganesh ◽  
Pragasam Viswanathan
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Acute Kidney Injury ◽  
Wistar Rats ◽  
Kidney Injury ◽  
Urinary Ngal ◽  
Tissue Lipid ◽  
Dihydroxyvitamin D3 ◽  
Tissue Lipid Peroxidation ◽  
Serum And Urine

Acute kidney injury causes significant morbidity and mortality. This experimental animal study investigated the simultaneous impact of iron and vitamin D on acute kidney injury induced by iohexol, an iodinated, non-ionic monomeric radiocontrast agent in Wistar rats. Out of 36 healthy male Wistar rats, saline was injected into six control rats (group 1) and iohexol into the remaining 30 experimental rats (groups 2 to 6 comprising six rats each). Biochemical, renal histological changes, and gene expression of iron-regulating proteins and 1 α-hydroxylase were analyzed. Urinary neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, urine protein, serum and urine catalytic iron, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and tissue lipid peroxidation were assayed. Rats injected with iohexol showed elevated urinary NGAL (11.94 ± 6.79 ng/mL), serum creatinine (2.92 ± 0.91 mg/dL), and urinary protein levels (11.03 ± 9.68 mg/mg creatinine) together with histological evidence of tubular injury and iron accumulation. Gene expression of iron-regulating proteins and 1 α-hydroxylase was altered. Serum and urine catalytic iron levels were elevated (0.57 ± 0.17; 48.95 ± 29.13 µmol/L) compared to controls (0.49 ± 0.04; 20.7 ± 2.62 µmol/L, P < 0.001). Urine catalytic iron positively correlated with tissue peroxidation (r = 0.469, CI 0.122 to 0.667, P = 0.004) and urinary NGAL (r = 0.788, CI 0.620 to 0.887, P < 0.001). 25-hydroxyvitamin D3 (61.58 ± 9.60 ng/mL) and 1,25-dihydroxyvitamin D3 (50.44 ± 19.76 pg/mL) levels increased simultaneously. In a multivariate linear regression analysis, serum iron, urine catalytic iron, and tissue lipid peroxidation independently and positively predicted urinary NGAL, an acute kidney injury biomarker. This study highlights the nephrotoxic potential of catalytic iron besides demonstrating a concurrent induction of vitamin D endogenously for possible renoprotection in acute kidney injury. Impact statement This work provides in-depth insights on catalytic iron-induced cytotoxicity and the resultant triggering of endogenous vitamin D synthesis in experimental acute kidney injury. Our results reveal significantly elevated levels of catalytic iron culminating in oxidant-mediated renal injury and a concomitant increase in 1,25-dihdyroxyvitamin D3 levels. Also, changes in other iron-related proteins including transferrin, ferritin, and hepcidin were observed both in the serum as well as in their mRNA expression. We consider all these findings vital since no connection between catalytic iron and vitamin D has been established so far. Furthermore, we believe that this work provides new and interesting results, with catalytic iron emerging as an important target in ameliorating renal cellular injury, possibly by timely administration of vitamin D. It also needs to be seen if these observations made in rats could be translated to humans by means of robust clinical trials.

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