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

Kidney Int. 2016 Nov;90(5):985-996. doi: 10.1016/j.kint.2016.05.019. Epub 2016 Jul 22.

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.

Keywords: FGF23; calcineurin; chronic kidney disease; hepatocytes; inflammation.

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cytokines / metabolism*
  • Fibroblast Growth Factors / metabolism*
  • Glucuronidase / metabolism
  • Hepatocytes / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Mice
  • NFATC Transcription Factors / metabolism
  • Phospholipase C gamma / metabolism
  • Primary Cell Culture
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism
  • Renal Insufficiency, Chronic / metabolism*
  • Signal Transduction

Substances

  • Cytokines
  • NFATC Transcription Factors
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Receptor, Fibroblast Growth Factor, Type 4
  • Calcineurin
  • Phospholipase C gamma
  • Glucuronidase
  • klotho protein