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Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism

Authors :
Bingbing Zhang
Florian Lang
Christoph Daniel
Bernat Elvira
Hajar Fahkri
Tak W. Mak
Michael Föller
Jillian Haight
Bernd J. Pichler
Julia G. Mannheim
Atsushi Hirao
Abul Fajol
Kerstin Amann
Nati Hernando
Source :
Pflügers Archiv - European Journal of Physiology. 467:1871-1880
Publication Year :
2014
Publisher :
Springer Science and Business Media LLC, 2014.

Abstract

Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1α-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1α-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by μCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1α-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression thereby impacting on calcium and phosphate metabolism.

Details

ISSN :
14322013 and 00316768
Volume :
467
Database :
OpenAIRE
Journal :
Pflügers Archiv - European Journal of Physiology
Accession number :
edsair.doi.dedup.....9b3796c8cabca951b4cb0d832e646755
Full Text :
https://doi.org/10.1007/s00424-014-1625-9