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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Singh, S; Grabner, A; Yanucil, C; Schramm, K; Czaya, B; Krick, S; Czaja, MJ; Bartz, R; Abraham, R; Di Marco, GS; Brand, M; Wolf, M; Faul, C

Published Date

  • November 2016

Published In

Volume / Issue

  • 90 / 5

Start / End Page

  • 985 - 996

PubMed ID

  • 27457912

Pubmed Central ID

  • 27457912

Electronic International Standard Serial Number (EISSN)

  • 1523-1755

Digital Object Identifier (DOI)

  • 10.1016/j.kint.2016.05.019

Language

  • eng

Conference Location

  • United States