Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice
Open Access
- 9 January 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (2), 812-822
- https://doi.org/10.1172/jci64093
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.Keywords
This publication has 76 references indexed in Scilit:
- Mineralocorticoid receptors in vascular function and diseaseMolecular and Cellular Endocrinology, 2012
- The Role of Phosphorus in the Development and Progression of Vascular CalcificationAmerican Journal of Kidney Diseases, 2011
- The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney diseaseBritish Journal of Clinical Pharmacology, 2011
- Cross Talk Between the Renin-Angiotensin-Aldosterone System and Vitamin D-FGF-23-klotho in Chronic Kidney DiseaseJournal of the American Society of Nephrology, 2011
- Klotho Deficiency Causes Vascular Calcification in Chronic Kidney DiseaseJournal of the American Society of Nephrology, 2011
- Eplerenone reverses spironolactone-induced painful gynaecomastia in cirrhoticsHepatology International, 2010
- Androgen Receptor-dependent Transactivation of Growth Arrest-specific Gene 6 Mediates Inhibitory Effects of Testosterone on Vascular CalcificationPublished by Elsevier BV ,2010
- Vascular CalcificationJournal of the American Society of Nephrology, 2009
- Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic ratsExperimental Physiology, 2008
- Amelioration of progressive renal injury by genetic manipulation of Klotho geneProceedings of the National Academy of Sciences of the United States of America, 2007