scholarly journals The Vitamin D Analog ED-71 Is a Potent Regulator of Intestinal Phosphate Absorption and NaPi-IIb

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5150-5156 ◽  
Author(s):  
Alex J. Brown ◽  
Fanjie Zhang ◽  
Cynthia S. Ritter
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Mineral Metabolism ◽  
Oral Treatment ◽  
Fold Increase ◽  
Alveolar Type ◽  
Mrna Levels ◽  
Potent Inducer ◽  
Vitamin D Analog ◽  
Fold Induction

Abstract The vitamin D analog ED-71 [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D3] has been approved for treatment of osteoporosis in Japan, but its effects on mineral metabolism have not been fully explored. We investigated the actions of ED-71 on phosphate (Pi) absorption and induction of the intestinal sodium/phosphate cotransporters. Oral treatment of vitamin D-deficient rats with ED-71 (20 pmol every other day for 8 d) produced a maximal 8-fold increase in duodenal Pi absorption, measured by the in situ loop method, whereas 1,25-dihyroxyvitamin D3 [1,25(OH)2D3], at doses up to 150 pmol, had no effect. This action of ED-71 was attributable to a dramatic 24-fold induction of sodium-dependent Pi transporter type IIb (NaPi-IIb) mRNA in the duodenum; Pit-1 and Pit-2 mRNA levels were not increased. In vitamin D-replete rats, ED-71 treatment (50 pmol) at 72 and 24 h before death increased NaPi-IIb mRNA in the duodenum and jejunum, but not the ileum, whereas 1,25(OH)2D3 at 1000 pmol was ineffective in all segments. Single oral doses of ED-71 increased mouse intestinal NaPi-IIb mRNA and protein between 6 and 24 h. Surprisingly, rat lung NaPi-IIb was not increased by ED-71, despite its coexpression with the vitamin D receptor in alveolar type II cells. However, ED-71 did not induce intestinal NaPi-IIb in vitamin D receptor-ablated mice. The greater potency of ED-71 than 1,25(OH)2D3 on NaPi-IIb appears to be due to much higher and more prolonged levels of ED-71 in the circulation. In summary, ED-71, due to its disparate pharmacokinetics, is a much more potent inducer of intestinal Pi absorption and NaPi-IIb than 1,25(OH)2D3, suggesting a role for this analog in the treatment of Pi-wasting disorders.

scholarly journals Intestinal Resistance to 1,25 Dihydroxyvitamin D in Mice Heterozygous for the Vitamin D Receptor Knockout Allele

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1396-1402 ◽  
Author(s):  
Yurong Song ◽  
James C. Fleet
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Time Course ◽  
Transient Receptor Potential ◽  
Gene Knockout ◽  
Mrna Levels ◽  
Wild Type ◽  
Calcium Diet ◽  
Low Calcium Diet ◽  
Low Calcium

We tested the hypothesis that low vitamin D receptor (VDR) level causes intestinal vitamin D resistance and intestinal calcium (Ca) malabsorption. To do so, we examined vitamin D regulated duodenal Ca absorption and gene expression [transient receptor potential channel, vallinoid subfamily member 6 (TRPV6), 24-hydroxylase, calbindin D9k (CaBP) mRNA, and CaBP protein] in wild-type mice and mice with reduced tissue VDR levels [i.e. heterozygotes for the VDR gene knockout (HT)]. Induction of 24-hydroxylase mRNA levels by 1,25 dihydroxyvitamin D3 [1,25(OH)2 D3] injection was significantly reduced in the duodenum and kidney of HT mice in both time-course and dose-response experiments. TRPV6 and CaBP mRNA levels in duodenum were significantly induced after 1,25(OH)2 D3 injection, but there was no difference in response between wild-type and HT mice. Feeding a low-calcium diet for 1 wk increased plasma PTH, renal 1α-hydroxylase (CYP27B1) mRNA level, and plasma 1,25(OH)2 D3, and this response was greater in HT mice (by 88, 55, and 37% higher, respectively). In contrast, duodenal TRPV6 and CaBP mRNA were not higher in HT mice fed the low-calcium diet. However, the response of duodenal Ca absorption and CaBP protein to increasing 1,25(OH)2 D3 levels was blunted by 40% in HT mice. Our data show that low VDR levels lead to resistance of intestinal Ca absorption to 1,25(OH)2 D3, and this resistance may be due to a role for the VDR (and VDR level) in the translation of CaBP.

scholarly journals Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians

2013 ◽  
Vol 169 (1) ◽  
pp. 109-116 ◽  
Author(s):  
Shweta Varshney ◽  
Sanjay Kumar Bhadada ◽  
Uma Nahar Saikia ◽  
Naresh Sachdeva ◽  
Arunanshu Behera ◽  
...  
Keyword(s):  
Vitamin D ◽  
Primary Hyperparathyroidism ◽  
Cyclin D1 ◽  
Vitamin D Receptor ◽  
Asian Indians ◽  
Parathyroid Tissue ◽  
Fold Change ◽  
Mrna Levels ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

BackgroundTo explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT).Materials and methodsForty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR.ResultsImmunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, bothVDRandCASRmRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) andCD1andPTHmRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue.PTHmRNA correlated with plasma PTH (r=0.864;P<0.001), but not with adenoma weight, whileCD1mRNA correlated with adenoma weight (r=0.715;P<0.001). There were no correlations betweenVDRandCASRmRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases inVDRandCASRmRNA expressions and the increases inPTHandCD1mRNA expressions.ConclusionsThe expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition,CD1expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.

scholarly journals The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Nakhoul Nakhoul ◽  
Tina Thawko ◽  
Evgeny Farber ◽  
Inbal Dahan ◽  
Hagar Tadmor ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Vitamin D ◽  
Diabetic Nephropathy ◽  
Vitamin D Receptor ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Active Vitamin ◽  
Active Vitamin D ◽  
Vitamin D Analog

Background. Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. Methods. Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. Results. Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. Conclusions. Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

The effect of a new vitamin D analog, 22-oxa-1?,25(OH)2D3, on bone mineral metabolism in normal male rats

1992 ◽  
Vol 50 (6) ◽  
pp. 521-523 ◽  
Author(s):  
Makoto Takizawa ◽  
Michael Fallon ◽  
Barry Stein ◽  
Sol Epstein
Keyword(s):  
Vitamin D ◽  
Bone Mineral ◽  
Mineral Metabolism ◽  
Male Rats ◽  
Normal Male ◽  
Bone Mineral Metabolism ◽  
Vitamin D Analog

The vitamin D receptor as a target for the treatment of breast cancer: Studies with the low calcemic vitamin D analog, inecalcitol.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e12011-e12011
Author(s):  
Alyson M. Murray ◽  
Stephen F. Madden ◽  
Naoise C Synnott ◽  
John Crown ◽  
Norma O'Donovan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analog ◽  
Cancer Studies

scholarly journals Role of the vitamin D receptor in FGF23 action on phosphate metabolism

2005 ◽  
Vol 390 (1) ◽  
pp. 325-331 ◽  
Author(s):  
Yoshio Inoue ◽  
Hiroko Segawa ◽  
Ichiro Kaneko ◽  
Setsuko Yamanaka ◽  
Kenichiro Kusano ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Fibroblast Growth Factor 23 ◽  
Mrna Levels ◽  
Dna Encoding ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Naked Dna ◽  
25 Hydroxyvitamin D

FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(−/−) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(−/−) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1α-hydroxylase mRNA levels in VDR(−/−) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(−/−) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1α-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.

scholarly journals Pregnancy Up-Regulates Intestinal Calcium Absorption and Skeletal Mineralization Independently of the Vitamin D Receptor

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 886-895 ◽  
Author(s):  
Neva J. Fudge ◽  
Christopher S. Kovacs
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Calcium Absorption ◽  
Fold Increase ◽  
Normal Diet ◽  
Intestinal Calcium Absorption ◽  
A Genome ◽  
Pregnancy And Lactation ◽  
Turnover Markers ◽  
Calbindin D

Without the vitamin D receptor (VDR), adult mammals develop reduced intestinal calcium absorption, rickets, and osteomalacia. Intestinal calcium absorption normally increases during pregnancy so that the mother can supply sufficient calcium to her fetuses. The maternal skeleton is rapidly resorbed during lactation to provide calcium needed for milk; that lost bone mineral content (BMC) is completely restored after weaning. We studied Vdr null mice to determine whether these adaptations during pregnancy and lactation require the VDR. Vdr nulls were severely rachitic at 10 wk of age on a normal diet. Pregnancy induced a 158% increase in Vdr null BMC to equal the pregnant wild-type (WT) value. Lactation caused BMC losses that were equal in Vdr nulls and WT. Vdr nulls recovered after weaning to a BMC 50% higher than before pregnancy and equal to WT. Additional analyses showed that during pregnancy, duodenal 45Ca absorption increased in Vdr nulls, secondary hyperparathyroidism lessened, bone turnover markers decreased, and osteoid became fully mineralized. A genome-wide microarray analysis of duodenal RNA found marked reduction of Trpv6 in Vdr nulls at baseline but a 13.5-fold increase during pregnancy. Calbindin D-9K (S100g) and Ca2+-ATPase (Pmca1) were not altered by pregnancy. Several other solute transporters increased during pregnancy in Vdr nulls. In summary, Vdr nulls adapt to pregnancy by up-regulating duodenal Trpv6 and intestinal 45Ca absorption, thereby enabling rapid normalization of BMC during pregnancy. These mice lactate normally and fully restore BMC after weaning. Therefore, VDR is not required for the skeletal adaptations during pregnancy, lactation, and after weaning.

scholarly journals Vitamin D Receptor Activators and Clinical Outcomes in Chronic Kidney Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Luciana Gravellone ◽  
Maria Antonietta Rizzo ◽  
Valentina Martina ◽  
Nicoletta Mezzina ◽  
Anna Regalia ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Vitamin D Receptor ◽  
Mineral Metabolism ◽  
Controlled Trial ◽  
Protective Role ◽  
Hemodialysis Patients ◽  
Vitamin D Metabolites ◽  
Beneficial Effects

Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.

Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort

2020 ◽  
pp. 1-14
Author(s):  
Nohela B. Arévalo ◽  
Daniela P. Castillo-Godoy ◽  
Italo Espinoza-Fuenzalida ◽  
Nicole K. Rogers ◽  
Gonzalo Farias ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Vitamin D Receptor ◽  
Mononuclear Cells ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Mrna Levels ◽  
Vdr Gene ◽  
Vdr Polymorphisms

Background: Amyloid-β peptide (Aβ) deposition in Alzheimer’s disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. Objective: To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aβ-transporters in peripheral blood mononuclear cells (PBMCs). Methods: VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aβ-transporters were evaluated in subgroups by qPCR. Results: Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aβ-transporters in both groups. Conclusion: We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

scholarly journals Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system

2006 ◽  
Vol 36 (3) ◽  
pp. 415-424 ◽  
Author(s):  
P Viganò ◽  
D Lattuada ◽  
S Mangioni ◽  
L Ermellino ◽  
M Vignali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Cycle Phase ◽  
Mrna Levels ◽  
Endometrial Cells ◽  
Immunological Mechanisms ◽  
Hormonal Modulation ◽  
Ectopic Endometrium

In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has potent anti-proliferative/immunomodulatory effects on various tissues. Consistently, the enzyme that catalyzes the synthesis of 1,25(OH)2D3, 1α-hydroxylase (1α-OHase) and the vitamin D receptor have a widespread tissue distribution. Among site-specific functions, the hormone has been suggested to be involved in uterine physiology. However, molecular analysis of the vitamin D system in normal endometrium throughout the menstrual cycle as well as its regulation in the context of endometrial physiological and pathological events have received very limited attention. Thus, we have studied expression, localization and regulation of 1α-OHase in human cycling and early pregnant endometrium. The capacity for 1α-hydroxylation and the presence of vitamin D receptor in endometrial cells have also been evaluated. The functional significance of these findings has been tested by evaluating gene expression of the catabolic enzyme, vitamin D 24-hydroxylase, and of the adhesion protein, osteopontin. Finally, to verify any potential dysfunction of the vitamin D system in endometriosis, a reproductive disease characterized by immune-mediated anomalies, we have analyzed expression of 1α-OHase in both eutopic and ectopic endometrium of affected patients. Results obtained showed that the active form of the 1α-OHase gene was expressed in human endometrial stromal cells independent of the cycle phase but with a significant increase in early pregnant decidua. A similar profile was observed for the protein, which was abundantly expressed in the cytoplasm of both endometrial stroma and epithelial glands. Both cycling and early pregnant endometrial cells also expressed the vitamin D receptor. In the same cells, 1α-OHase mRNA levels were significantly stimulated by the pro-inflammatory cytokine interleukin (IL)-1β (50 and 500 pg/ml) while addition of the active form of the hormone could modulate both CYP24 and osteopontin gene expression. The 1α-OHase gene was also expressed in ectopic endometrium and its levels were increased in proliferative phase cultures derived from patients with endometriosis. Human cycling endometrium may be included among the extrarenal sites able to synthesize vitamin D. The IL-1β-mediated induction of 1α-OHase gene and the hormonal modulation of osteopontin support a role for the hormone in the immunological mechanisms underlying uterine function. Abnormalities of this system are present in endometriosis.

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