TY - JOUR
T1 - Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice
AU - Voelkl, Jakob
AU - Alesutan, Ioana
AU - Leibrock, Christina B.
AU - Quintanilla-Martinez, Leticia
AU - Kuhn, Volker
AU - Feger, Martina
AU - Mia, Sobuj
AU - Ahmed, Mohamed S E
AU - Rosenblatt, Kevin P.
AU - Kuro-O, Makoto
AU - Lang, Florian
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84873371137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873371137&partnerID=8YFLogxK
U2 - 10.1172/JCI64093
DO - 10.1172/JCI64093
M3 - Article
C2 - 23298834
AN - SCOPUS:84873371137
SN - 0021-9738
VL - 123
SP - 812
EP - 822
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -