Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells

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

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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.

Original languageEnglish (US)
Article number2059
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Cytochrome P-450 CYP11B2
Vascular Smooth Muscle
Smooth Muscle Myocytes
Blood Vessels
Phosphates
Hyperphosphatemia
Vascular Calcification
Spironolactone
Aldosterone
Mineralocorticoid Receptors
Cell Nucleus Active Transport
Chronic Renal Insufficiency
Pharmacology
Mortality

ASJC Scopus subject areas

  • General

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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.

In: Scientific Reports, Vol. 7, No. 1, 2059, 01.12.2017.

Research output: Contribution to journalArticle

Alesutan, I, Voelkl, J, Feger, M, Kratschmar, DV, Castor, T, Mia, S, Sacherer, M, Viereck, R, Borst, O, Leibrock, C, Gawaz, M, Kuro-O, M, Pilz, S, Tomaschitz, A, Odermatt, A, Pieske, B, Wagner, CA & Lang, F 2017, 'Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells', Scientific Reports, vol. 7, no. 1, 2059. https://doi.org/10.1038/s41598-017-01882-2
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. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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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.",
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AU - Kratschmar, Denise V.

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AU - Mia, Sobuj

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AU - Viereck, Robert

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AU - Leibrock, Christina

AU - Gawaz, Meinrad

AU - Kuro-O, Makoto

AU - Pilz, Stefan

AU - Tomaschitz, Andreas

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AU - Lang, Florian

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AB - 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.

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