Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease

• Type of Material: Article
• Authors: Saurav Singh, University of Miami; Alexander Grabner, University of Miami; Christopher Yanucil, University of Miami; Karla Schramm, University of Miami; Brian Czaya, University of Miami; Stefanie Krick, University of Miami; Mark Czaja, Emory University; Rene Bartz, U3 Pharma GmbH; Reimar Abraham, U3 Pharma GmbH; Giovana Seno Di Marco, University Hospital Münster; Marcus Brand, University Hospital Münster; Myles Wolf, Northwestern University; Christian Faul, University of Miami
• Language: English
• Date: 2016-11
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 International Society of Nephrology
• Final Published Version (URL): http://dx.doi.org/10.1016/j.kint.2016.05.019
• Title of Journal or Parent Work: Kidney International
• ISSN: 0085-2538
• Volume: 90
• Issue: 5
• Start Page: 985
• End Page: 996
• Grant/Funding Information: This study was supported by the Stifterverband für die Deutsche Wissenschaft and Simon-Claussen-Stiftung (H 1405409999915626 to M.B.), the Deutsche Forschungs Gemeinschaft (GR 4228/1-1 to A.G.), Roche (A.G.), the American Heart Association (A.G., C.F.), the American Diabetes Association (C.F.), U3 Pharma GmbH, Germany (C.F.), and grants F31DK10236101 (K.S.), R01DK044234 (M.J.C.), R01DK061498 (M.J.C.), R01AA022601 (M.J.C.) R01DK076116 (M.W.), K24DK093723 (M.W.) and R01HL128714 (C.F.) from the National Institutes of Health.
• Keywords: Science & Technology; Urology & Nephrology; Life Sciences & Biomedicine; CARDIAC-HYPERTROPHY; hepatocytes; SIGNAL-TRANSDUCTION; FGF23; chronic kidney disease; STAGE RENAL-DISEASE; inflammation; C-REACTIVE PROTEIN; BILE-ACID SYNTHESIS; LEFT-VENTRICULAR HYPERTROPHY; FACTOR RECEPTOR; MINERAL METABOLISM; HEMODIALYSIS-PATIENTS; HEPATOCELLULAR-CARCINOMA; calcineurin
• Research Categories: Biology, Cell; Biology, Anatomy

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 a ctivating 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.