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Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells
Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldoster...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435689/ https://www.ncbi.nlm.nih.gov/pubmed/28515448 http://dx.doi.org/10.1038/s41598-017-01882-2 |
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author | Alesutan, Ioana Voelkl, Jakob Feger, Martina Kratschmar, Denise V. Castor, Tatsiana Mia, Sobuj Sacherer, Michael Viereck, Robert Borst, Oliver Leibrock, Christina Gawaz, Meinrad Kuro-o, Makoto Pilz, Stefan Tomaschitz, Andreas Odermatt, Alex Pieske, Burkert Wagner, Carsten A. Lang, Florian |
author_facet | Alesutan, Ioana Voelkl, Jakob Feger, Martina Kratschmar, Denise V. Castor, Tatsiana Mia, Sobuj Sacherer, Michael Viereck, Robert Borst, Oliver Leibrock, Christina Gawaz, Meinrad Kuro-o, Makoto Pilz, Stefan Tomaschitz, Andreas Odermatt, Alex Pieske, Burkert Wagner, Carsten A. Lang, Florian |
author_sort | Alesutan, Ioana |
collection | PubMed |
description | Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs). High phosphate concentrations up-regulated aldosterone synthase (CYP11B2) expression in HAoSMCs. Silencing and deficiency of CYP11B2 in VSMCs ameliorated phosphate-induced osteogenic reprogramming and calcification. Phosphate treatment was followed by nuclear export of APEX1, a CYP11B2 transcriptional repressor. APEX1 silencing up-regulated CYP11B2 expression and stimulated osteo-/chondrogenic transformation. APEX1 overexpression blunted the phosphate-induced osteo-/chondrogenic transformation and calcification of HAoSMCs. Cyp11b2 expression was higher in aortic tissue of hyperphosphatemic klotho-hypomorphic (kl/kl) mice than in wild-type mice. In adrenalectomized kl/kl mice, spironolactone treatment still significantly ameliorated aortic osteoinductive reprogramming. Our findings suggest that VSMCs express aldosterone synthase, which is up-regulated by phosphate-induced disruption of APEX1-dependent gene suppression. Vascular CYP11B2 may contribute to stimulation of VSMCs osteo-/chondrogenic transformation during hyperphosphatemia. |
format | Online Article Text |
id | pubmed-5435689 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-54356892017-05-18 Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells Alesutan, Ioana Voelkl, Jakob Feger, Martina Kratschmar, Denise V. Castor, Tatsiana Mia, Sobuj Sacherer, Michael Viereck, Robert Borst, Oliver Leibrock, Christina Gawaz, Meinrad Kuro-o, Makoto Pilz, Stefan Tomaschitz, Andreas Odermatt, Alex Pieske, Burkert Wagner, Carsten A. Lang, Florian Sci Rep Article Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs). High phosphate concentrations up-regulated aldosterone synthase (CYP11B2) expression in HAoSMCs. Silencing and deficiency of CYP11B2 in VSMCs ameliorated phosphate-induced osteogenic reprogramming and calcification. Phosphate treatment was followed by nuclear export of APEX1, a CYP11B2 transcriptional repressor. APEX1 silencing up-regulated CYP11B2 expression and stimulated osteo-/chondrogenic transformation. APEX1 overexpression blunted the phosphate-induced osteo-/chondrogenic transformation and calcification of HAoSMCs. Cyp11b2 expression was higher in aortic tissue of hyperphosphatemic klotho-hypomorphic (kl/kl) mice than in wild-type mice. In adrenalectomized kl/kl mice, spironolactone treatment still significantly ameliorated aortic osteoinductive reprogramming. Our findings suggest that VSMCs express aldosterone synthase, which is up-regulated by phosphate-induced disruption of APEX1-dependent gene suppression. Vascular CYP11B2 may contribute to stimulation of VSMCs osteo-/chondrogenic transformation during hyperphosphatemia. Nature Publishing Group UK 2017-05-17 /pmc/articles/PMC5435689/ /pubmed/28515448 http://dx.doi.org/10.1038/s41598-017-01882-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Alesutan, Ioana Voelkl, Jakob Feger, Martina Kratschmar, Denise V. Castor, Tatsiana Mia, Sobuj Sacherer, Michael Viereck, Robert Borst, Oliver Leibrock, Christina Gawaz, Meinrad Kuro-o, Makoto Pilz, Stefan Tomaschitz, Andreas Odermatt, Alex Pieske, Burkert Wagner, Carsten A. Lang, Florian Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title | Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title_full | Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title_fullStr | Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title_full_unstemmed | Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title_short | Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
title_sort | involvement of vascular aldosterone synthase in phosphate-induced osteogenic transformation of vascular smooth muscle cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435689/ https://www.ncbi.nlm.nih.gov/pubmed/28515448 http://dx.doi.org/10.1038/s41598-017-01882-2 |
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