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

Saurav Singh, Alexander Grabner, Christopher Yanucil, Karla Schramm, Brian Czaya, Stefanie Krick, Mark J. Czaja, Rene Bartz, Reimar Abraham, Giovana S. Di Marco, Marcus Brand, Myles Wolf, Christian H Faul

Research output: Contribution to journalArticle

112 Scopus citations

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.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Jan 28 2016

Keywords

  • Calcineurin
  • Chronic kidney disease
  • FGF23
  • Hepatocytes
  • Inflammation

ASJC Scopus subject areas

  • Nephrology

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    Singh, S., Grabner, A., Yanucil, C., Schramm, K., Czaya, B., Krick, S., Czaja, M. J., Bartz, R., Abraham, R., Di Marco, G. S., Brand, M., Wolf, M., & Faul, C. H. (Accepted/In press). Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney International. https://doi.org/10.1016/j.kint.2016.05.019