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

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.

• Authors: Hajar Fahkri, Bingbing Zhang, Abul Fajol, Nati Hernando, Bernat Elvira, Julia G Mannheim, Bernd J Pichler, Christoph Daniel, Kerstin Amann, Atsushi Hirao, Jillian Haight, Tak W Mak, Florian Lang, Michael Föller
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 467 Issue 9 Pg. 1871-80 (Sep 2015) ISSN: 1432-2013 [Electronic] Germany
• PMID: 25319519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FGF23 protein, human
• Fgf23 protein, mouse
• Phosphates
• Fibroblast Growth Factor-23
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
• Checkpoint Kinase 2
• Chek2 protein, mouse
• Glucuronidase
• Klotho Proteins
• Calcitriol
• Calcium

Topics

• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (metabolism)
• Animals
• Blotting, Western
• Bone Density (physiology)
• Calcitriol (biosynthesis)
• Calcium (metabolism)
• Checkpoint Kinase 2 (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Fibroblast Growth Factor-23
• Gene Expression Regulation (physiology)
• Glucuronidase (metabolism)
• HEK293 Cells
• Humans
• Kidney (metabolism)
• Klotho Proteins
• Mice
• Mice, Knockout
• Phosphates (metabolism)
• Real-Time Polymerase Chain Reaction
• X-Ray Microtomography