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Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice
Jakob Voelkl, … , Makoto Kuro-o, Florian Lang
Jakob Voelkl, … , Makoto Kuro-o, Florian Lang
Published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):812-822. https://doi.org/10.1172/JCI64093.
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Research Article Article has an altmetric score of 22

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

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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.

Authors

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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Figure 8

Effects of aldosterone/spironolactone in high phosphate conditions and of FGF23 during aldosterone treatment on PIT1 and CBFA1 expression in HAoSMCs.

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Effects of aldosterone/spironolactone in high phosphate conditions and o...
Arithmetic mean ± SEM (n = 6–9; arbitrary units) of mRNA levels encoding (A) PIT1 and (B) CBFA1 in HAoSMCs after 24-hour treatments with vehicle alone (Control, white bars), with 2 mM β-glycerophosphate (Pi, dark gray bars), or with cotreatment with 100 nM aldosterone (Pi+Aldo, black bars), 100 nM aldosterone/10 μM spironolactone (Pi+Aldo+Spiro, light gray bars), or 10 μM spironolactone (Pi+Spiro, light gray bars). (C) Representative original bands of KLOTHO (KL) and calibrator/control GAPDH mRNA expression. (D) Arithmetic mean ± SEM (n = 6; arbitrary units) of KL mRNA levels in HAoSMCs after 48-hour silencing with 10 nM of negative control siRNA (Neg. siRNA, white bar) or with 10 nM klotho siRNA (KL siRNA, black bar). Arithmetic mean ± SEM (n = 8–9; arbitrary units) of mRNA levels encoding (E) PIT1 and (F) CBFA1 in HAoSMCs after 48-hour silencing with 10 nM negative control siRNA (white bars) or with 10 nM klotho siRNA (black bars), without or with 100 nM aldosterone and 5 ng/ml FGF23 (Aldo+FGF23) treatment for 24 hours. *P < 0.05, **P < 0.01, ***P < 0.001, compared with control-treated HAoSMCs. †P < 0.05, †††P < 0.001, compared with HAoSMCs treated with 2 mM β-glycerophosphate or aldosterone alone. ##P < 0.01, ###P < 0.001, compared with HAoSMCs treated with 2 mM β-glycerophosphate and 100 nM aldosterone or HAoSMCs silenced with negative control siRNA and treated with 100 nM aldosterone and 5 ng/ml FGF23.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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