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

Czaya, B.; Heitman, K.; Campos, I.; Yanucil, C.; Kentrup, D.; Westbrook, D.; Gutierrez, O.; Babitt, J.; Jung, G.; Salusky, I.; Hanudel, M.; Faul, C.

doi:10.1101/2021.10.22.465390

bioRxiv · 10.1101/2021.10.22.465390

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

Czaya, B.·Heitman, K.·Campos, I.·Yanucil, C.·Kentrup, D.·Westbrook, D.·Gutierrez, O.·Babitt, J.·Jung, G.·Salusky, I.·Hanudel, M.·Faul, C.

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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.

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Czaya, B., Heitman, K., Campos, I., Yanucil, C., Kentrup, D., Westbrook, D., Gutierrez, O., Babitt, J., Jung, G., Salusky, I., Hanudel, M., Faul, C.. 2021-10-22. Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling. https://doi.org/10.1101/2021.10.22.465390

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