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J Mol Med (Berl). 2016 Jan;94(1):95-106. doi: 10.1007/s00109-015-1331-x. Epub 2015 Aug 27.

Acetazolamide sensitive tissue calcification and aging of klotho-hypomorphic mice.

Author information

1
Department of Physiology, Physiologisches Institut der Universität Tübingen, Gmelinstr 5, D-72076, Tübingen, Germany.
2
Department of Pathology, Liebermeisterstr. 8, University of Tübingen, Tübingen, Germany.
3
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Röntgenweg 13, 72076, Tübingen, Germany.
4
Center for Clinical Proteomics, the Brown Foundation Institute of Molecular Medicine, 1825 Pressler Street, SRB, Suite 330E, Houston, TX, USA.
5
Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
6
Department of Physiology, Physiologisches Institut der Universität Tübingen, Gmelinstr 5, D-72076, Tübingen, Germany. florian.lang@uni-tuebingen.de.

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, Ca(2+), 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, Ca(2+), 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.

KEYWORDS:

1,25(OH)2D3; Acetazolamide; Acidosis; Calcification; Calcium; Phosphate

PMID:
26307633
DOI:
10.1007/s00109-015-1331-x
[Indexed for MEDLINE]

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