Document Detail

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice.
MedLine Citation:
PMID:  23298834     Owner:  NLM     Status:  MEDLINE    
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.
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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-08-21    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  812-22     Citation Subset:  AIM; IM    
Department of Physiology, University of Tübingen, Tübingen, Germany.
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MeSH Terms
Aldosterone / pharmacology
Cell Differentiation / drug effects
Cells, Cultured
Fibroblast Growth Factors / metabolism
Glucuronidase / deficiency*,  genetics
Mice, Knockout
Osteoblasts / drug effects,  metabolism,  pathology
RNA, Messenger / genetics,  metabolism
Renal Insufficiency, Chronic / complications,  metabolism,  pathology
Signal Transduction / drug effects
Spironolactone / pharmacology*
Transcription Factor Pit-1 / genetics,  metabolism*
Vascular Calcification / etiology,  metabolism,  pathology,  prevention & control*
Reg. No./Substance:
0/POU1F1 protein, human; 0/Pit1 protein, mouse; 0/RNA, Messenger; 0/Transcription Factor Pit-1; 0/fibroblast growth factor 23; 52-01-7/Spironolactone; 52-39-1/Aldosterone; 62031-54-3/Fibroblast Growth Factors; EC; EC protein
Comment In:
Nat Rev Nephrol. 2013 Mar;9(3):125   [PMID:  23358423 ]

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