Different vitamin D receptor agonists exhibit differential effects on endothelial function and aortic gene expression in 5/6 nephrectomized rats

Vitamin D receptor (VDR) activation therapy is associated with cardiovascular/survival benefit in chronic kidney disease (CKD), but the mechanism of action is not well understood. The aim of this study is to investigate how uremia affects gene expression in aorta and whether VDR activation modulates the uremic effect. DNA microarray technology was used to assess the gene expression profile in aorta prepared from SHAM and 5/6 nephrectomized (NX) rat, a model of Stage 4/5 CKD, treated with or without 0.17 μg/kg paricalcitol, a VDR activator. As expected, paricalcitol at 0.17 μg/kg after two weeks of treatment effectively suppressed serum parathyroid hormone (PTH); no significant difference was observed in ionized calcium or serum phosphorus. Uremia exhibited a significant effect on the gene expression pattern in the aorta, affecting 468 sequences ( ≥1.5-fold changes with p<0.01 vs. SHAM). When the criteria were tightened to ≥ 2-fold changes with p<0.01, uremia still affected 135 target sequences in the rat aorta with 63 up-regulated and 72 down-regulated. Target genes fell into various categories including metabolism and cellular metabolism. Paricalcitol treatment normalized 95 out of the 135 sequences affected by uremia; many of the genes were related to mitochondrial function and oxidative stress. As a follow-up to the microarray analysis, endothelial function was examined. Uremia significantly affected aortic relaxation (−50.0 ± 7.4% in NX rats vs. −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation response to acetylcholine (Ach) at 30 μM was improved to −58.2 ± 6.0%, −77.5 ± 7.3% and −90.5 ± 4.0% in NX rats treated with paricalcitol at 0.021, 0.042 and 0.083 μg/kg for two weeks, respectively, while blood pressure and heart rate were not changed. PTH suppression alone didn’t improve endothelial function since cinacalcet, a calcimimetic targeting calcium sensing receptor, suppressed PTH without affecting endothelial-dependent vasorelaxation. In conclusion, VDR activation by paricalcitol modulates the effect of uremia on aortic gene expression and endothelial function independent of PTH and blood pressure control, which may be one of the mechanisms responsible for paricalcitol’s cardiovascular benefit in CKD.

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Lithocholic Acid-Based Design of Noncalcemic Vitamin D Receptor Agonists

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.104878 ◽

2021 ◽

pp. 104878

Author(s):

Sunil Gaikwad ◽

Carmen M. González ◽

Daniel Vilariño ◽

Gonzalo Lasanta ◽

Carmen Villaverde ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Lithocholic Acid ◽

Receptor Agonists

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A Positive GATA Element and a Negative Vitamin D Receptor-Like Element Control Atrial Chamber-Specific Expression of a Slow Myosin Heavy-Chain Gene during Cardiac Morphogenesis

Molecular and Cellular Biology ◽

10.1128/mcb.18.10.6023 ◽

1998 ◽

Vol 18 (10) ◽

pp. 6023-6034 ◽

Cited By ~ 42

Author(s):

Gang Feng Wang ◽

William Nikovits ◽

Mark Schleinitz ◽

Frank E. Stockdale

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Vitamin D Receptor ◽

Heavy Chain ◽

Inhibitory Activity ◽

Binding Motif ◽

Specific Expression ◽

Ventricular Cardiomyocytes ◽

Slow Myosin Heavy Chain ◽

Slow Myhc

ABSTRACT We have used the slow myosin heavy chain (MyHC) 3 gene to study the molecular mechanisms that control atrial chamber-specific gene expression. Initially, slow MyHC 3 is uniformly expressed throughout the tubular heart of the quail embryo. As cardiac development proceeds, an anterior-posterior gradient of slow MyHC 3 expression develops, culminating in atrial chamber-restricted expression of this gene following chamberization. Two cis elements within the slow MyHC 3 gene promoter, a GATA-binding motif and a vitamin D receptor (VDR)-like binding motif, control chamber-specific expression. The GATA element of the slow MyHC 3 is sufficient for expression of a heterologous reporter gene in both atrial and ventricular cardiomyocytes, and expression of GATA-4, but not Nkx2-5 or myocyte enhancer factor 2C, activates reporter gene expression in fibroblasts. Equivalent levels of GATA-binding activity were found in extracts of atrial and ventricular cardiomyocytes from embryonic chamberized hearts. These observations suggest that GATA factors positively regulate slow MyHC 3 gene expression throughout the tubular heart and subsequently in the atria. In contrast, an inhibitory activity, operating through the VDR-like element, increased in ventricular cardiomyocytes during the transition of the heart from a tubular to a chambered structure. Overexpression of the VDR, acting via the VDR-like element, duplicates the inhibitory activity in ventricular but not in atrial cardiomyocytes. These data suggest that atrial chamber-specific expression of the slow MyHC 3 gene is achieved through the VDR-like inhibitory element in ventricular cardiomyocytes at the time distinct atrial and ventricular chambers form.

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Presence of gene expression of vitamin D receptor and 24-hydroxylase in OK cells

FEBS Letters ◽

10.1016/0014-5793(94)80627-6 ◽

1994 ◽

Vol 337 (1) ◽

pp. 48-51 ◽

Cited By ~ 3

Author(s):

Eiji Ishimura ◽

Shigeichi Shoji ◽

Hidenori Koyama ◽

Masaaki Inaba ◽

Yoshiki Nishizawa ◽

...

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Vitamin D Receptor ◽

Ok Cells

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The noncalcemic vitamin D analogues EB1089 and 22-oxacalcitriol interact with the vitamin D receptor and suppress parathyroid hormone-related peptide gene expression

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(96)03994-9 ◽

1997 ◽

Vol 127 (1) ◽

pp. 99-108 ◽

Cited By ~ 16

Author(s):

Miriam Falzon

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Parathyroid Hormone ◽

Vitamin D Receptor ◽

Related Peptide ◽

Vitamin D Analogues ◽

Parathyroid Hormone Related Peptide ◽

Peptide Gene

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Alternative splicing of the vitamin D receptor modulates target gene expression and promotes ligand-independent functions

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2018.12.009 ◽

2019 ◽

Vol 364 ◽

pp. 55-67 ◽

Cited By ~ 1

Author(s):

Andrew J. Annalora ◽

Marija Jozic ◽

Craig B. Marcus ◽

Patrick L. Iversen

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Alternative Splicing ◽

Vitamin D Receptor ◽

Target Gene ◽

Target Gene Expression ◽

Independent Functions

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Regulation of target gene expression by the vitamin D receptor - an update on mechanisms

Reviews in Endocrine and Metabolic Disorders ◽

10.1007/s11154-011-9198-9 ◽

2011 ◽

Vol 13 (1) ◽

pp. 45-55 ◽

Cited By ~ 69

Author(s):

J. Wesley Pike ◽

Mark B. Meyer ◽

Kathleen A. Bishop

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Vitamin D Receptor ◽

Target Gene ◽

Target Gene Expression

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The effectiveness of nutritional vitamin D supplementation and selective vitamin D receptor agonists treatment on secondary hyperparathyroidism in chronic kidney diseases patients

Osteoporosis and Bone Diseases ◽

10.14341/osteo9879 ◽

2018 ◽

Vol 21 (2) ◽

pp. 12-22 ◽

Cited By ~ 1

Author(s):

Lilit V. Egshatyan ◽

Natalya G. Mokrisheva

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Secondary Hyperparathyroidism ◽

Vitamin D Receptor ◽

Vitamin D Supplementation ◽

Target Range ◽

Receptor Agonists ◽

Stage 4 ◽

Calcium Phosphorus ◽

Phosphorus Levels

Background: secondary hyperparathyroidism (SHPT) is an early complication of chronic kidney disease (CKD). Maintaining the level of 25(OH)D and parathyroid hormone concentrations in the target range reduce its associated complications (fractures and cardiovascular calcification). Aims: to examine the effectiveness of vitamin D supplementation and selective vitamin D receptor agonists treatment on SHPT in CKD. Material and methods: prospective observational study to evaluate the efficacy and safety of vitamin D therapy SHPT in 54 in patients with CKD. The first phase (24 weeks) – treatment of suboptimal 25-hydroxycalciferol (25(OH)D) levels. The second (16 weeks) – treatment colecalciferol-resistant SHPT by combination of cholecalciferol with paricalcitol. Blood samples were taken to assess parathyroid hormone (PTH), 25(OH)D, creatinine, calcium, phosphorus levels and calcium excretion. Results: After 8 weeks of cholecalciferol treatment all patients achieved 25(OH)D levels above 20 ng/ml, however 78% of patients still had SHPT. After 16 weeks, the decrease of PTH was achieved in all patients, but significantly only in patients with CKD 2 (19.2%, p< 0.01) and 3 (31%, p <0.05), compared with CKD 4 (17%, p >0.05). After 24 weeks of therapy, PTH normalized in all patients with CKD 2, in 15 (79%) with CKD 3 and in 9 (50%) patients with CKD 4. Cholecalciferol treatment resulted in a substantial increase in 25(OH)D levels with minimal or no impact on calcium, phosphorus levels and kidney function. After 24 weeks we initiated combination therapy (cholecalciferol and paricalcitol) for patients with colecalciferol-resistant SHPT (n=13). PTH levels decreased from 149.1±13.4 to 118.2±14.1 pg/ml at 8 weeks, and to 93.1±9.7 pg/ml (p <0.05) at 16 weeks of treatment. No significant differences in serum calcium, phosphorus or urinary calcium levels. Normalization of PTH was achieved in all patients with CKD 3 and in 8 patients with stage 4. One patient with CKD 4 needed an increase in paricalcitol dose. Conclusion: Cholecalciferol can be used in correcting vitamin D deficiency in patients with all stages of CKD, however, its effectiveness in reducing PTH in stage 4 is limited. Selective analogs, such as paricalcitol, were well-tolerated and effectively decreased PTH levels.

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