title: 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.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Hajar
authors.initials: H
authors.lastname: Fahkri
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zhang
authors.forename: Abul
authors.initials: A
authors.lastname: Fajol
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
authors.forename: Bernat
authors.initials: B
authors.lastname: Elvira
authors.forename: Julia G
authors.initials: JG
authors.lastname: Mannheim
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000502:physiology*; D002117:Calcitriol / Q000096:biosynthesis*; D002118:Calcium / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation / Q000502:physiology; D005966:Glucuronidase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol; D002118:Calcium