TY - JOUR
T1 - Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease
AU - Singh, Saurav
AU - Grabner, Alexander
AU - Yanucil, Christopher
AU - Schramm, Karla
AU - Czaya, Brian
AU - Krick, Stefanie
AU - Czaja, Mark J.
AU - Bartz, Rene
AU - Abraham, Reimar
AU - Di Marco, Giovana S.
AU - Brand, Marcus
AU - Wolf, Myles
AU - Faul, Christian
N1 - Funding Information:
This study was supported by the Stifterverband für die Deutsche Wissenschaft and Simon-Claussen-Stiftung (H 1405409999915626 to MB), the Deutsche Forschungs Gemeinschaft (GR 4228/1-1 to AG), Roche (AG), the American Heart Association (AG, CF), the American Diabetes Association (CF), U3 Pharma GmbH, Germany (CF), and grants F31DK10236101 (KS), R01DK044234 (MJC), R01DK061498 (MJC), R01AA022601 (MJC), R01DK076116 (MW), K24DK093723 (MW), and R01HL128714 (CF) from the National Institutes of Health.
Publisher Copyright:
© 2016 International Society of Nephrology
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - FGF23
KW - calcineurin
KW - chronic kidney disease
KW - hepatocytes
KW - inflammation
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U2 - 10.1016/j.kint.2016.05.019
DO - 10.1016/j.kint.2016.05.019
M3 - Article
C2 - 27457912
AN - SCOPUS:84979011044
VL - 90
SP - 985
EP - 996
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -