title: Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice.
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.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Voelkl
authors.forename: Ioana
authors.initials: I
authors.lastname: Alesutan
authors.forename: Christina B
authors.initials: CB
authors.lastname: Leibrock
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Volker
authors.initials: V
authors.lastname: Kuhn
authors.forename: Martina
authors.initials: M
authors.lastname: Feger
authors.forename: Sobuj
authors.initials: S
authors.lastname: Mia
authors.forename: Mohamed S E
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Rosenblatt
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism*; D061205:Vascular Calcification / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000450:Aldosterone; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D012333:RNA, Messenger; D013148:Spironolactone; D050817:Transcription Factor Pit-1; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C494187:POU1F1 protein, human; C494185:Pou1f1 protein, mouse