Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

Jakob Voelkl, Ioana Alesutan, Christina B. Leibrock, Leticia Quintanilla-Martinez, Volker Kuhn, Martina Feger, Sobuj Mia, Mohamed S E Ahmed, Kevin P. Rosenblatt, Makoto Kuro-O, Florian Lang

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Abstract

Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH) 2D3] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH)2D3, FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.

Original languageEnglish (US)
Pages (from-to)812-822
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number2
DOIs
StatePublished - Feb 1 2013

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Spironolactone
Blood Vessels
Aldosterone
Smooth Muscle Myocytes
Transcription Factors
Mineralocorticoid Receptor Antagonists
Hyperphosphatemia
Calcifediol
Messenger RNA
Hyperaldosteronism
Chronic Kidney Failure
Alkaline Phosphatase
Growth
calcium phosphate

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Voelkl, J., Alesutan, I., Leibrock, C. B., Quintanilla-Martinez, L., Kuhn, V., Feger, M., ... Lang, F. (2013). Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. Journal of Clinical Investigation, 123(2), 812-822. https://doi.org/10.1172/JCI64093

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. / Voelkl, Jakob; Alesutan, Ioana; Leibrock, Christina B.; Quintanilla-Martinez, Leticia; Kuhn, Volker; Feger, Martina; Mia, Sobuj; Ahmed, Mohamed S E; Rosenblatt, Kevin P.; Kuro-O, Makoto; Lang, Florian.

In: Journal of Clinical Investigation, Vol. 123, No. 2, 01.02.2013, p. 812-822.

Research output: Contribution to journalArticle

Voelkl, J, Alesutan, I, Leibrock, CB, Quintanilla-Martinez, L, Kuhn, V, Feger, M, Mia, S, Ahmed, MSE, Rosenblatt, KP, Kuro-O, M & Lang, F 2013, 'Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice', Journal of Clinical Investigation, vol. 123, no. 2, pp. 812-822. https://doi.org/10.1172/JCI64093
Voelkl J, Alesutan I, Leibrock CB, Quintanilla-Martinez L, Kuhn V, Feger M et al. Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. Journal of Clinical Investigation. 2013 Feb 1;123(2):812-822. https://doi.org/10.1172/JCI64093
Voelkl, Jakob ; Alesutan, Ioana ; Leibrock, Christina B. ; Quintanilla-Martinez, Leticia ; Kuhn, Volker ; Feger, Martina ; Mia, Sobuj ; Ahmed, Mohamed S E ; Rosenblatt, Kevin P. ; Kuro-O, Makoto ; Lang, Florian. / Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 2. pp. 812-822.
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