Spironolactone Ameliorates PIT1-dependent Vascular Osteoinduction in Klotho-hypomorphic Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2013 Jan 10

PMID 23298834

Citations 77

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

Affiliations

Soon will be listed here.

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.

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