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

90 Citations (Scopus)

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

Fingerprint

Chronic Renal Insufficiency
Hepatocytes
Protein Isoforms
Fibroblast Growth Factor Receptors
Inflammation
C-Reactive Protein
Cytokines
Liver
Receptor, Fibroblast Growth Factor, Type 4
Osteocytes
Blocking Antibodies
Calcineurin
Nephrectomy
Knockout Mice
Anti-Inflammatory Agents
Phosphates
fibroblast growth factor 23
Hormones
Kidney
Mortality

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Singh, S., Grabner, A., Yanucil, C., Schramm, K., Czaya, B., Krick, S., ... 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

Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. / Singh, Saurav; Grabner, Alexander; Yanucil, Christopher; Schramm, Karla; Czaya, Brian; Krick, Stefanie; Czaja, Mark J.; Bartz, Rene; Abraham, Reimar; Di Marco, Giovana S.; Brand, Marcus; Wolf, Myles; Faul, Christian H.

In: Kidney International, 28.01.2016.

Research output: Contribution to journalArticle

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, CH 2016, '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
Singh, Saurav ; Grabner, Alexander ; Yanucil, Christopher ; Schramm, Karla ; Czaya, Brian ; Krick, Stefanie ; Czaja, Mark J. ; Bartz, Rene ; Abraham, Reimar ; Di Marco, Giovana S. ; Brand, Marcus ; Wolf, Myles ; Faul, Christian H. / Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. In: Kidney International. 2016.
@article{31149e0883af4576965e00f9d49aa06b,
title = "Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease",
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 = "Calcineurin, Chronic kidney disease, FGF23, Hepatocytes, Inflammation",
author = "Saurav Singh and Alexander Grabner and Christopher Yanucil and Karla Schramm and Brian Czaya and Stefanie Krick and Czaja, {Mark J.} and Rene Bartz and Reimar Abraham and {Di Marco}, {Giovana S.} and Marcus Brand and Myles Wolf and Faul, {Christian H}",
year = "2016",
month = "1",
day = "28",
doi = "10.1016/j.kint.2016.05.019",
language = "English (US)",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",

}

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 H

PY - 2016/1/28

Y1 - 2016/1/28

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 - Calcineurin

KW - Chronic kidney disease

KW - FGF23

KW - Hepatocytes

KW - Inflammation

UR - http://www.scopus.com/inward/record.url?scp=84979011044&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979011044&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2016.05.019

DO - 10.1016/j.kint.2016.05.019

M3 - Article

C2 - 27457912

AN - SCOPUS:84979011044

JO - Kidney International

JF - Kidney International

SN - 0085-2538

ER -