title: FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues.
abstract: The mitochondrial enzyme 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by the CYP27B1 gene, converts 25OHD to the biological active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Renal 1α-hydroxylase activity is the principal determinant of the circulating 1,25(OH)2D concentration and enzyme activity is tightly regulated by several factors. Fibroblast growth factor-23 (FGF-23) decreases serum 1,25(OH)2D concentrations by suppressing CYP27B1 mRNA abundance in mice. In extra-renal tissues, 1α-hydroxylase is responsible for local 1,25(OH)2D synthesis, which has important paracrine actions, but whether FGF-23 regulates CYP27B1 gene expression in extra-renal tissues is unknown. We sought to determine whether FGF-23 regulates CYP27B1 transcription in the kidney and whether extra-renal tissues are target sites for FGF-23-induced suppression of CYP27B1. In HEK293 cells transfected with the human CYP27B1 promoter, FGF-23 suppressed promoter activity by 70%, and the suppressive effect was blocked by CI-1040, a specific inhibitor of extracellular signal regulated kinase 1/2. To examine CYP27B1 transcriptional activity in vivo, we crossed fgf-23 null mice with mice bearing the CYP27B1 promoter-driven luciferase transgene (1α-Luc). In the kidney of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity was increased by 3-fold compared to that in wild-type/1α-Luc mice. Intraperitoneal injection of FGF-23 suppressed renal CYP27B1 promoter activity and protein expression by 26% and 60% respectively, and the suppressive effect was blocked by PD0325901, an ERK1/2 inhibitor. These findings provide evidence that FGF-23 suppresses CYP27B1 transcription in the kidney. Furthermore, we demonstrate that in FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA abundance are increased in several extra-renal sites. In the heart of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA were 2- and 5-fold higher, respectively, than in control mice. We also observed a 3- to 10-fold increase in CYP27B1 mRNA abundance in the lung, spleen, aorta and testis of FGF-23 null/1α-Luc mice. Thus, we have identified novel extra-renal target sites for FGF-23-mediated regulation of CYP27B1.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ankanee
authors.initials: A
authors.lastname: Chanakul
authors.forename: Martin Y H
authors.initials: MY
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Louw
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Armbrecht
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Portale
authors.forename: Farzana
authors.initials: F
authors.lastname: Perwad
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D020935:MAP Kinase Signaling System; D051379:Mice; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
references.citation: Am J Physiol Renal Physiol. 2007 Nov;293(5):F1577-83
references.pmid: 17699549
references.citation: Clin Biochem Rev. 2010 Nov;31(4):129-38
references.pmid: 21170259
references.citation: J Steroid Biochem Mol Biol. 1992 Dec;43(8):1073-81
references.pmid: 22217851
references.citation: J Steroid Biochem Mol Biol. 2012 May;130(1-2):73-80
references.pmid: 22326730
references.citation: J Clin Endocrinol Metab. 1974 Dec;39(6):1045-56
references.pmid: 4372244
references.citation: J Clin Endocrinol Metab. 1987 Dec;65(6):1201-9
references.pmid: 3119653
references.citation: J Bone Miner Res. 2004 Mar;19(3):429-35
references.pmid: 15040831
references.citation: J Endocrinol. 2007 Oct;195(1):125-31
references.pmid: 17911404
references.citation: Ann Intern Med. 1984 Jan;100(1):59-61
references.pmid: 6546329
references.citation: J Biol Chem. 1972 Dec 10;247(23):7528-32
references.pmid: 4404596
references.citation: Kidney Int. 2008 Jul;74(2):170-9
references.pmid: 18385669
references.citation: Arch Biochem Biophys. 2008 Sep 1;477(1):33-42
references.pmid: 18593564
references.citation: Circulation. 2005 Apr 5;111(13):1666-71
references.pmid: 15795327
references.citation: Mol Cell Endocrinol. 2008 Mar 26;285(1-2):1-9
references.pmid: 18313834
references.citation: Endocrinology. 2002 Aug;143(8):3179-82
references.pmid: 12130585
references.citation: J Clin Endocrinol Metab. 2007 Aug;92(8):3177-82
references.pmid: 17488797
references.citation: Am J Hum Genet. 1998 Dec;63(6):1694-702
references.pmid: 9837822
references.citation: Nature. 1970 Nov 21;228(5273):764-6
references.pmid: 4319631
references.citation: Biochem Biophys Res Commun. 1998 Aug 10;249(1):11-6
references.pmid: 9705822
references.citation: J Clin Invest. 2007 Dec;117(12):4003-8
references.pmid: 17992255
references.citation: J Biol Chem. 2003 Mar 14;278(11):9843-9
references.pmid: 12519781
references.citation: Mol Endocrinol. 1997 Dec;11(13):1961-70
references.pmid: 9415400
references.citation: Circulation. 2012 May 8;125(18):2243-55
references.pmid: 22492635
references.citation: J Clin Invest. 1987 Jun;79(6):1706-12
references.pmid: 3034981
references.citation: FASEB J. 2006 Apr;20(6):720-2
references.pmid: 16436465
references.citation: Science. 1997 Sep 19;277(5333):1827-30
references.pmid: 9295274
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12920-5
references.pmid: 9371776
references.citation: Nature. 1978 Nov 16;276(5685):287-9
references.pmid: 714161
references.citation: J Bone Miner Res. 1997 Oct;12(10):1552-9
references.pmid: 9333115
references.citation: Mol Endocrinol. 2004 Oct;18(10):2440-50
references.pmid: 15243130
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):330-3
references.pmid: 17223550
references.citation: J Bone Miner Metab. 2010 Mar;28(2):117-30
references.pmid: 20107849
references.citation: J Clin Invest. 2004 Feb;113(4):561-8
references.pmid: 14966565
references.citation: Arch Biochem Biophys. 2003 Jan 15;409(2):298-304
references.pmid: 12504896
references.citation: Endocrinology. 2012 Apr;153(4):1806-16
references.pmid: 22334725
references.citation: Kidney Int. 2010 Jul;78(2):140-5
references.pmid: 20182414
references.citation: J Biol Chem. 1985 Sep 25;260(21):11488-92
references.pmid: 4044567
references.citation: Endocrinology. 2005 Dec;146(12):5358-64
references.pmid: 16123154
references.citation: J Clin Invest. 1983 Nov;72(5):1856-60
references.pmid: 6688814
references.citation: DNA Cell Biol. 1997 Dec;16(12):1499-507
references.pmid: 9428799
references.citation: N Engl J Med. 2011 Aug 4;365(5):410-21
references.pmid: 21675912
references.citation: Biochem Biophys Res Commun. 1997 Oct 20;239(2):527-33
references.pmid: 9344864
references.citation: Proc Natl Acad Sci U S A. 2004 May 18;101(20):7711-5
references.pmid: 15128933
references.citation: N Engl J Med. 2003 Jul 31;349(5):446-56
references.pmid: 12890843
references.citation: J Biol Chem. 2006 Mar 10;281(10):6120-3
references.pmid: 16436388
references.citation: J Clin Invest. 1986 Aug;78(2):557-66
references.pmid: 2426308
references.citation: Matrix Biol. 2004 Nov;23(7):421-32
references.pmid: 15579309
references.citation: Biochem Biophys Res Commun. 2004 Feb 6;314(2):409-14
references.pmid: 14733920
references.citation: Science. 1971 Jun 18;172(3989):1232-4
references.pmid: 4325104
references.citation: Reproduction. 2012 Aug;144(2):135-52
references.pmid: 22635305
references.citation: J Bone Miner Res. 2011 Aug;26(8):1883-90
references.pmid: 21472778
references.citation: Am J Physiol. 1990 Jan;258(1 Pt 1):E134-42
references.pmid: 2154115
references.citation: Endocrinology. 2002 Feb;143(2):587-95
references.pmid: 11796514
references.citation: J Biol Chem. 1981 Aug 10;256(15):7738-40
references.pmid: 6973569
references.citation: J Mol Endocrinol. 2005 Feb;34(1):237-45
references.pmid: 15691891
references.citation: Nature. 2006 Dec 7;444(7120):770-4
references.pmid: 17086194
references.citation: J Biol Chem. 2002 Oct 4;277(40):36987-90
references.pmid: 11956203
references.citation: J Clin Invest. 2011 Nov;121(11):4393-408
references.pmid: 21985788
references.citation: Nucleic Acids Res. 2007;35(8):2734-47
references.pmid: 17426122
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):533-7
references.pmid: 17276054
references.citation: J Am Soc Nephrol. 2005 Apr;16(4):1115-25
references.pmid: 15728786
references.citation: J Biol Chem. 1991 Apr 25;266(12):7774-8
references.pmid: 1708392
references.citation: Am J Physiol. 1997 Apr;272(4 Pt 2):H1751-8
references.pmid: 9139959
references.citation: Kidney Int. 2006 Aug;70(4):654-9
references.pmid: 16807549
references.citation: Int J Biochem Cell Biol. 2002 Aug;34(8):921-30
references.pmid: 12007630
references.citation: Hypertension. 2008 Dec;52(6):1106-12
references.pmid: 18936343
references.citation: J Clin Endocrinol Metab. 2002 Jun;87(6):2424-30
references.pmid: 12050193
references.citation: J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):139-42
references.pmid: 15225761
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6988-93
references.pmid: 10359826
references.citation: J Am Soc Nephrol. 2009 May;20(5):955-60
references.pmid: 19357251
references.citation: Proc Natl Acad Sci U S A. 1981 Feb;78(2):1199-203
references.pmid: 6940135