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FGFR4 does not contribute to progression of chronic kidney disease

In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independent...

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Autores principales: Taylor, Ashlee, Yanucil, Christopher, Musgrove, John, Shi, Melody, Ide, Shintaro, Souma, Tomokazu, Faul, Christian, Wolf, Myles, Grabner, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773883/
https://www.ncbi.nlm.nih.gov/pubmed/31575945
http://dx.doi.org/10.1038/s41598-019-50669-0
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author Taylor, Ashlee
Yanucil, Christopher
Musgrove, John
Shi, Melody
Ide, Shintaro
Souma, Tomokazu
Faul, Christian
Wolf, Myles
Grabner, Alexander
author_facet Taylor, Ashlee
Yanucil, Christopher
Musgrove, John
Shi, Melody
Ide, Shintaro
Souma, Tomokazu
Faul, Christian
Wolf, Myles
Grabner, Alexander
author_sort Taylor, Ashlee
collection PubMed
description In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independently of α-klotho, the canonical co-receptor for FGF23 in the kidney, which stimulates left ventricular hypertrophy and hepatic production of inflammatory cytokines. FGF23 has also been shown to independently predict progression of renal disease, however, whether FGF23 and FGFR4 also contribute to CKD remains unknown. Here, we generated a mouse model with dual deletions of FGFR4 and α-klotho, and we induced CKD in mice with either global deletion or constitutive activation of FGFR4. We demonstrate that FGF23 is not capable of inducing phosphaturia via FGFR4 and that FGFR4 does not promote or mitigate renal injury in animal models of CKD. Taken together our results suggest FGFR4 inhibition as a safe alternative strategy to target cardiovascular disease and chronic inflammation in patients with CKD without interrupting the necessary phosphaturic effects of FGF23.
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spelling pubmed-67738832019-10-04 FGFR4 does not contribute to progression of chronic kidney disease Taylor, Ashlee Yanucil, Christopher Musgrove, John Shi, Melody Ide, Shintaro Souma, Tomokazu Faul, Christian Wolf, Myles Grabner, Alexander Sci Rep Article In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independently of α-klotho, the canonical co-receptor for FGF23 in the kidney, which stimulates left ventricular hypertrophy and hepatic production of inflammatory cytokines. FGF23 has also been shown to independently predict progression of renal disease, however, whether FGF23 and FGFR4 also contribute to CKD remains unknown. Here, we generated a mouse model with dual deletions of FGFR4 and α-klotho, and we induced CKD in mice with either global deletion or constitutive activation of FGFR4. We demonstrate that FGF23 is not capable of inducing phosphaturia via FGFR4 and that FGFR4 does not promote or mitigate renal injury in animal models of CKD. Taken together our results suggest FGFR4 inhibition as a safe alternative strategy to target cardiovascular disease and chronic inflammation in patients with CKD without interrupting the necessary phosphaturic effects of FGF23. Nature Publishing Group UK 2019-10-01 /pmc/articles/PMC6773883/ /pubmed/31575945 http://dx.doi.org/10.1038/s41598-019-50669-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Taylor, Ashlee
Yanucil, Christopher
Musgrove, John
Shi, Melody
Ide, Shintaro
Souma, Tomokazu
Faul, Christian
Wolf, Myles
Grabner, Alexander
FGFR4 does not contribute to progression of chronic kidney disease
title FGFR4 does not contribute to progression of chronic kidney disease
title_full FGFR4 does not contribute to progression of chronic kidney disease
title_fullStr FGFR4 does not contribute to progression of chronic kidney disease
title_full_unstemmed FGFR4 does not contribute to progression of chronic kidney disease
title_short FGFR4 does not contribute to progression of chronic kidney disease
title_sort fgfr4 does not contribute to progression of chronic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773883/
https://www.ncbi.nlm.nih.gov/pubmed/31575945
http://dx.doi.org/10.1038/s41598-019-50669-0
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