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

Fahkri H, Zhang B, Fajol A, Hernando N, Elvira B, Mannheim JG, Pichler BJ, Daniel C, Amann KU, Hirao A, Haight J, Mak TW, Lang F, Foeller M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Pflügers Archiv: European Journal of Physiology Springer

Book Volume: 467

Pages Range: 1871-80

Journal Issue: 9

DOI: 10.1007/s00424-014-1625-9

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 1?-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1?-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 1?-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by ?CT 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 1?-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 1?-hydroxylase expression thereby impacting on calcium and phosphate metabolism.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Kerstin Ute Amann Department of Nephropathology

Involved external institutions

Eberhard Karls Universität Tübingen DE Germany (DE) University Health Network (UHN) CA Canada (CA) Kanazawa University / 金沢大学 JP Japan (JP) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH)

How to cite

APA:

Fahkri, H., Zhang, B., Fajol, A., Hernando, N., Elvira, B., Mannheim, J.G.,... Foeller, M. (2015). Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism. Pflügers Archiv: European Journal of Physiology, 467(9), 1871-80. https://doi.org/10.1007/s00424-014-1625-9

MLA:

Fahkri, Hajar, et al. "Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism." Pflügers Archiv: European Journal of Physiology 467.9 (2015): 1871-80.

BibTeX: Download