Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells
Abstract 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...
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2017
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oai:doaj.org-article:c635e27a35b04458b69aff88f7a050b42021-12-02T16:07:57ZInvolvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells10.1038/s41598-017-01882-22045-2322https://doaj.org/article/c635e27a35b04458b69aff88f7a050b42017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01882-2https://doaj.org/toc/2045-2322Abstract 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.Ioana AlesutanJakob VoelklMartina FegerDenise V. KratschmarTatsiana CastorSobuj MiaMichael SachererRobert ViereckOliver BorstChristina LeibrockMeinrad GawazMakoto Kuro-oStefan PilzAndreas TomaschitzAlex OdermattBurkert PieskeCarsten A. WagnerFlorian LangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) |
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Medicine R Science Q Ioana Alesutan Jakob Voelkl Martina Feger Denise V. Kratschmar Tatsiana Castor Sobuj Mia Michael Sacherer Robert Viereck Oliver Borst Christina Leibrock Meinrad Gawaz Makoto Kuro-o Stefan Pilz Andreas Tomaschitz Alex Odermatt Burkert Pieske Carsten A. Wagner Florian Lang Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells |
| description |
Abstract 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 |
article |
| author |
Ioana Alesutan Jakob Voelkl Martina Feger Denise V. Kratschmar Tatsiana Castor Sobuj Mia Michael Sacherer Robert Viereck Oliver Borst Christina Leibrock Meinrad Gawaz Makoto Kuro-o Stefan Pilz Andreas Tomaschitz Alex Odermatt Burkert Pieske Carsten A. Wagner Florian Lang |
| author_facet |
Ioana Alesutan Jakob Voelkl Martina Feger Denise V. Kratschmar Tatsiana Castor Sobuj Mia Michael Sacherer Robert Viereck Oliver Borst Christina Leibrock Meinrad Gawaz Makoto Kuro-o Stefan Pilz Andreas Tomaschitz Alex Odermatt Burkert Pieske Carsten A. Wagner Florian Lang |
| author_sort |
Ioana Alesutan |
| title |
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_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_sort |
involvement of vascular aldosterone synthase in phosphate-induced osteogenic transformation of vascular smooth muscle cells |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/c635e27a35b04458b69aff88f7a050b4 |
| work_keys_str_mv |
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| _version_ |
1718384683980423168 |