title: Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease.
abstract: Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature that predicts poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 coreceptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Saurav
authors.initials: S
authors.lastname: Singh
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grabner
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yanucil
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Czaya
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krick
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Czaja
authors.affiliation: U3 Pharma GmbH, Martinsried, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Bartz
authors.affiliation: U3 Pharma GmbH, Martinsried, Germany.
authors.forename: Reimar
authors.initials: R
authors.lastname: Abraham
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, Germany.
authors.forename: Giovana S
authors.initials: GS
authors.lastname: Di Marco
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Brand
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA. Electronic address: cfaul@med.miami.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D050778:NFATC Transcription Factors; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051499:Receptor, Fibroblast Growth Factor, Type 4; D019703:Calcineurin; D051966:Phospholipase C gamma; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: FGF23; calcineurin; chronic kidney disease; hepatocytes; inflammation