Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

Abstract
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Abstract

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

Data availability

All data generated and analyzed during this study is available through Dryad.

The following data sets were generated

1. Faul C
(2022) Data from: Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling full source data
Dryad Digital Repository, doi:10.5061/dryad.6t1g1jx0f.

https://dx.doi.org/10.5061/dryad.6t1g1jx0f

Article and author information

Author details

Brian Czaya

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States

Competing interests
No competing interests declared.
Kylie Heitman

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-5345-2727
Isaac Campos

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
No competing interests declared.
Christopher Yanucil

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
No competing interests declared.
Dominik Kentrup

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
No competing interests declared.
David Westbrook

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
No competing interests declared.
Orlando Gutierrez

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

Competing interests
Orlando Gutierrez, has received honoraria and grant support from Akebia and Amgen, grant support from GSK, honoraria from Ardelyx, Reata, and AstraZeneca, and serves on the Data Monitoring Committee for QED.
Jodie L Babitt

Division of Nephrology, Massachusetts General Hospital, Boston, United States

Competing interests
Jodie L Babitt, has ownership interest in Ferrumax Pharmaceuticals and has been a consultant for Incyte Corporation, and Alnylam Pharmaceuticals.
Grace Jung

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, United States

Competing interests
No competing interests declared.
Isidro B Salusky

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States

Competing interests
No competing interests declared.
Mark Hanudel

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States

Competing interests
No competing interests declared.
Christian Faul

Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

For correspondence
cfaul@uabmc.edu

Competing interests
Christian Faul, has served as a consultant for Bayer and Calico Labs, and he is the founder and currently the CSO of a startup biotech company (Alpha Young LLC)u.

"This ORCID iD identifies the author of this article:" 0000-0002-7512-0977

Funding

National Institutes of Health (F31-DK-117550)

Brian Czaya

National Institutes of Health (F31-DK-115074)

Christopher Yanucil

National Institutes of Health (R01-HL-128714; R01-HL-145528)

Christian Faul

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal protocols and experimental procedures for adenine diet in FGFR4+/+ and FGFR4-/- mice, graded phosphate diets in FGFR4+/+ and FGFR4-/- mice, low phosphate diets in COL4A3+/+ and COL4A3-/- mice and primary hepatocyte isolations from wild-type C57BL/6J mice, were approved by the Institutional Animal Care and Use Committees (IACUC) at the University of Alabama Birmingham School of Medicine (#22089). All animals were maintained in a ventilated rodent-housing system with temperature-controlled environments (22-23{degree sign}C) with a 12-hour light/dark cycle and allowed ad libitum access to food and water. All protocols adhered to the Guide for Care and Use of Laboratory Animals to minimize pain and suffering. No animals were excluded from analysis.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.