Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis

Panizo, Sara; Carrillo-López, Natalia; Naves-Díaz, Manuel; Solache-Berrocal, Guillermo; Martínez-Arias, Laura; Rodrigues-Díez, Raúl R.; Fernández-Vázquez, Amalia; Martı́nez-Salgado, Carlos; Ruíz-Ortega, Marta; Dusso, Adriana; Cannata‐Andía, Jorge B.; Rodríguez, Isabel

doi:10.1093/ndt/gfx060

Cited by 45 publications

(29 citation statements)

References 49 publications

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“…Of interest, VD failed to significantly modify VDR mRNA expression, which reinforces that VD inhibits the proteasomal degradation of VDR [19], a process that may be overactive in fibroblasts from the CD-damaged tissue. However, the possibility that VD down-regulates the expression of miRNAs involved in VDR reduction, as recently reported in lung fibroblasts and cardiac fibrosis [33,34], cannot be ruled out. Of interest, the reduced VDR levels detected in fibroblasts from damaged tissue of CD patients paralleled with an enhanced migration of these cells, and VD significantly prevented the enhanced migration.…”

Section: Discussionmentioning

confidence: 89%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.

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Section: Discussionmentioning

confidence: 89%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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“…Recently, some studies found associations between 1,25(OH) 2 D 3 and cardiovascular disease (CVD), lung disease, and tuberculosis. 34,35 Panizo et al 36 found that in uremic cardiomyopathy, activation of 1,25(OH) 2 D 3 receptors weakens myocardial fibrosis by increasing the expression of some proteins, including MMP-2. In addition, supplementation of vitamin D in streptozotocin-induced diabetic mice improves endothelial function, 37 and induces increased expression of VEGF in vascular smooth muscle cells (VSMCs) by binding to the VDR, which acts as a transcription factor for the VEGF promoter.…”

Section: Discussionmentioning

confidence: 99%

1,25(OH)2D3 Strengthens the Vasculogenesis of Multipotent Mesenchymal Stromal Cells from Rat Bone Marrow by Regulating the PI3K/AKT Pathway

Weng

Lin

et al. 2020

DDDT

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Background: Multipotent mesenchymal stromal cells (MSCs) have recently been reported to promote vasculogenesis by differentiating into endothelial cells and releasing numerous cytokines and paracrine factors. However, due to low cell activity, their potential for clinical application is not very satisfactory. This study aimed to explore the effects and mechanisms of 1,25-dihydroxyvitamin D (1,25(OH) 2 D 3) on the vasculogenesis of MSCs. Methods: MSCs were isolated from the femurs and tibias of rats and characterized by flow cytometry. After treatment with different concentrations of 1,25(OH) 2 D 3 (0 µM, 0.1 µM and 1 µM), the proliferation of MSCs was analyzed by Cell Counting Kit-8 (CCK-8), and the migratory capability was measured by Transwell assays and cell scratch tests. Capillary-like structure formation was observed by using Matrigel. Western blotting was used to detect the expression of FLK-1 and vWF to investigate the differentiation of MSCs into endothelial cells. Western blotting and gelatin zymography were used to detect the expression and activities of VEGF, MMP-2 and MMP-9 secreted by MSCs under the influence of 1,25(OH) 2 D 3. Finally, the VDR antagonist pyridoxal-5-phosphate (P5P) and the PI3K/AKT pathway inhibitor LY294002 were utilized to test the phosphorylation levels of key kinases in the PI3K/AKT pathway by Western blotting and the formation of capillary-like structures in Matrigel. Results: The proliferation and migratory capability of MSCs and the ability of MSCs to form a tube-like structure in Matrigel were enhanced after treatment with 1,25(OH) 2 D 3. Moreover, MSCs treated with 1,25(OH) 2 D 3 showed high expression of vWF and Flk-1. There was a significant increase in the expression of VEGF, MMP-2 and MMP-9 secreted by MSCs treated with 1,25(OH) 2 D 3, as well as in the activity of MMP-2 and MMP-9. The phosphorylation level of AKT increased with time after 1,25(OH) 2 D 3 treatment, while LY294002 weakened AKT phosphorylation. In addition, the ability to form capillary-like structures was reduced when the VDR and PI3K/AKT pathways were blocked. Conclusion: This study confirmed that 1,25(OH) 2 D 3 treatment can strengthen the ability of MSCs to promote vasculogenesis in vitro, and the mechanism may be related to the activation of the PI3K/AKT pathway.

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“…VDR activators (such as calcitriol and paricalcitol) can inhibit the expressions of miR-29b and miR-30c in nephrectomized rats. These miRNAs seem to act on COL1A1, MMP-2, and CTGF expression, attenuating cardiac fibrosis [ 141 ]. In humans with moderate chronic kidney disease, paricalcitol treatment for 12 weeks reduces cytokines and microRNAs involved in atherosclerosis and inflammation [ 142 ].…”

Section: Microrna Nutrients Inflammation and Chronic Diseasesmentioning

confidence: 99%

Nutrimiromics: Role of microRNAs and Nutrition in Modulating Inflammation and Chronic Diseases

et al. 2017

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Nutrimiromics studies the influence of the diet on the modification of gene expression due to epigenetic processes related to microRNAs (miRNAs), which may affect the risk for the development of chronic diseases. miRNAs are a class of non-coding endogenous RNA molecules that are usually involved in post-transcriptional gene silencing by inducing mRNA degradation or translational repression by binding to a target messenger RNA. They can be controlled by environmental and dietary factors, particularly by isolated nutrients or bioactive compounds, indicating that diet manipulation may hold promise as a therapeutic approach in modulating the risk of chronic diseases. This review summarizes the evidence regarding the influence of nutrients and bioactive compounds on the expression of miRNAs related to inflammation and chronic disease in several models (cell culture, animal models, and human trials).

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Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis

Abstract: VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

Cited by 45 publications

References 49 publications

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

<p>1,25(OH)<sub>2</sub>D<sub>3</sub> Strengthens the Vasculogenesis of Multipotent Mesenchymal Stromal Cells from Rat Bone Marrow by Regulating the PI3K/AKT Pathway</p>

Nutrimiromics: Role of microRNAs and Nutrition in Modulating Inflammation and Chronic Diseases

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