title: Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism.
abstract: Calcitriol, a powerful regulator of phosphate metabolism and immune response, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney and macrophages. Renal 1α-hydroxylase expression is suppressed by Klotho and FGF23, the expression of which is stimulated by calcitriol. Interferon γ (INFγ) regulates 1α-hydroxylase expression in macrophages through transcription factor interferon regulatory factor-1. INFγ-signaling includes Janus kinase 3 (JAK3) but a role of JAK3 in the regulation of 1α-hydroxylase expression and mineral metabolism has not been shown. Thus, the impact of JAK3 deficiency on calcitriol formation and phosphate metabolism was measured. Renal interferon regulatory factor-1 and 1α-hydroxylase transcript levels, serum calcitriol and FGF23 levels, intestinal phosphate absorption as well as absolute and fractional renal phosphate excretion were significantly higher in jak3 knockout than in wild-type mice. Coexpression of JAK3 increased the phosphate-induced current in renal sodium-phosphate cotransporter-expressing Xenopus oocytes. Thus, JAK3 is a powerful regulator of 1α-hydroxylase expression and phosphate transport. Its deficiency leads to marked derangement of phosphate metabolism.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Anja T
authors.initials: AT
authors.lastname: Umbach
authors.affiliation: 1] Department of Physiology, University of Tübingen, Tübingen, Germany [2] Department of Molecular Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Nephropathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Abul
authors.initials: A
authors.lastname: Fajol
authors.affiliation: Proteome Center, University of Tübingen, Tübingen, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Hosseinzadeh
authors.affiliation: 1] Department of Physiology, University of Tübingen, Tübingen, Germany [2] Novartis Oncology, Novartis International AG, Hyderabad, India.
authors.forename: Shefalee K
authors.initials: SK
authors.lastname: Bhavsar
authors.affiliation: Department of Molecular Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: C-Thomas
authors.initials: CT
authors.lastname: Bock
authors.affiliation: Department of Molecular Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.affiliation: Department of Radiology, University of Tübingen, Tübingen, Germany.
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.affiliation: Department of Nephropathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Amann
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000032:analysis / Q000235:genetics*; D000818:Animals; D064026:Calbindins / Q000235:genetics; D002117:Calcitriol / Q000096:biosynthesis / Q000097:blood*; D005243:Feces / Q000737:chemistry; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D050856:Interferon Regulatory Factor-1 / Q000032:analysis / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D053616:Janus Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000737:chemistry / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000201:enzymology; D010710:Phosphates / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D015854:Up-Regulation; D014981:Xenopus
chemical_list: D064026:Calbindins; C000717428:Fgf23 protein, mouse; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010710:Phosphates; D012333:RNA, Messenger; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D053616:Janus Kinase 3; D002117:Calcitriol