Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice

Christina B. Leibrock, Ioana Alesutan, Jakob Voelkl, Diana Michael, Tatsiana Castor, Ursula Kohlhofer, Leticia Quintanilla-Martinez, Laura Kübler, Julia G. Mannheim, Bernd J. Pichler, Kevin P. Rosenblatt, Makoto Kuro-o, Florian Lang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Abstract: Klotho, a protein expressed mainly in the kidney, is required for the inhibitory effect of FGF23 on renal 1,25(OH)2D3 formation. Klotho counteracts vascular calcification and diverse age-related disorders. Klotho-hypomorphic mice (kl/kl) suffer from severe vascular calcification and rapid aging. The calcification is at least in part caused by excessive 1,25(OH)2D3, Ca2+, and phosphate concentrations in blood, which trigger osteogenic signaling including upregulation of alkaline phosphatase (Alpl). As precipitation of calcium and phosphate is fostered by alkaline pH, extracellular acidosis could counteract tissue calcification. In order to induce acidosis, acetazolamide was added to drinking water (0.8 g/l) of kl/kl and wild-type mice. As a result, acetazolamide treatment of kl/kl mice partially reversed the growth deficit, tripled the life span, almost completely reversed the calcifications in trachea, lung, kidney, stomach, intestine, and vascular tissues, the excessive aortic alkaline phosphatase mRNA levels and the plasma concentrations of osteoprotegerin, osteopontin as well as fetuin-A, without significantly decreasing FGF23, 1,25(OH)2D3, Ca2+, and phosphate plasma concentrations. In primary human aortic smooth muscle cells, acidotic environment prevented phosphate-induced alkaline phosphatase mRNA expression. The present study reveals a completely novel effect of acetazolamide, i.e., interference with osteoinductive signaling and tissue calcification in kl/kl mice. Key messages: Klotho deficient (kl/kl) mice suffer from hyperphosphatemia with dramatic tissue calcification.Acetazolamide (ACM) treatment partially reversed the growth deficit of kl/kl mice.In kl/kl mice, ACM reversed tissue calcification despite continued hyperphosphatemia.ACM tripled the life span of kl/kl mice.In human aortic smooth muscle cells, low extracellular pH prevented osteogenic signaling.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalJournal of Molecular Medicine
Volume94
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • 1,25(OH)D
  • Acetazolamide
  • Acidosis
  • Calcification
  • Calcium
  • Phosphate

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice'. Together they form a unique fingerprint.

Cite this