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Author Notes:

Correspondence should be addressed to: Christian Faul, PhD, 1580 NW 10th Avenue (R-762); Batchelor Bldg. 626, Miami, FL, USA 33136, Telephone: 305-243-3206; Fax 305-243-3209; cfaul@med.miami.edu

Saurav Singh and Alexander Grabner contributed equally.

Disclosure: Dr. Faul has served as a consultant or received honoraria from Ultragenyx and has received research support from U3 Pharma GmbH.

Dr. Czaja has served as a consultant or received honoraria from Genzyme/Sanofi and Verlyx Pharma and has received research support from Verlyx Pharma.

Dr. Wolf has served as a consultant or received honoraria from Ultragenyx, Amgen, Keryx, Lutipold, Opko, Pfizer and Sanofi.

All other authors have declared that no conflict of interest exists.

Drs. Bartz and Abraham are employees of U3Pharma GmbH.

Subjects:

Research Funding:

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
  • Life Sciences & Biomedicine
  • Urology & Nephrology
  • calcineurin
  • chronic kidney disease
  • FGF23
  • hepatocytes
  • inflammation
  • STAGE RENAL-DISEASE
  • LEFT-VENTRICULAR HYPERTROPHY
  • BILE-ACID SYNTHESIS
  • C-REACTIVE PROTEIN
  • FACTOR RECEPTOR
  • HEPATOCELLULAR-CARCINOMA
  • HEMODIALYSIS-PATIENTS
  • CARDIAC-HYPERTROPHY
  • SIGNAL-TRANSDUCTION
  • MINERAL METABOLISM

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

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Journal Title:

Kidney International

Volume:

Volume 90, Number 5

Publisher:

, Pages 985-996

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 International Society of Nephrology

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