Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling
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.
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Data from: Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling full source dataDryad Digital Repository, doi:10.5061/dryad.6t1g1jx0f.
Article and author information
Author details
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.
Reviewing Editor
- Dolores Shoback, University of California, San Francisco, United States
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.
Version history
- Received: October 17, 2021
- Preprint posted: October 22, 2021 (view preprint)
- Accepted: March 17, 2022
- Accepted Manuscript published: March 18, 2022 (version 1)
- Version of Record published: March 29, 2022 (version 2)
Copyright
© 2022, Czaya et al.
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.
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