Abstract: PO0324
Hyperphosphatemia Contributes to Inflammation, Iron Dysregulation, and Skeletal Muscle Wasting
Session Information
- Bone and Mineral Metabolism: Basic
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Czaya, Brian A., Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
- Heitman, Kylie, Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
- Campos, Isaac D., Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
- Yanucil, Christopher, Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
- Kentrup, Dominik, Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
- Faul, Christian, Univeristy of Alabama at Birmingham, Birmingham, Alabama, United States
Background
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that promotes phosphate (Pi) excretion. In patients with chronic kidney disease (CKD), serum levels of Pi & FGF23 gradually rise as renal function declines & associates with various pathologies such as systemic inflammation, anemia, vascular calcification & muscle wasting. Our previous studies have showed FGF23 induces inflammatory cytokine expression by targeting hepatocytes via FGF receptor 4 (FGFR4). Other studies have shown Pi accelerates vascular calcification. However, whether Pi contributes to inflammation, anemia or skeletal muscle wasting remains unclear. Here we compare the effects of Pi versus FGF23 to determine their contributions towards these CKD-associated pathologies, utilizing in vivo & in vitro models.
Methods
We subject mice with global FGFR4 deletion & wild-type littermates to an increasing dietary Pi load (0.7%, 2.0%, or 3.0%) or an adenine-rich diet (CKD model) to examine systemic inflammation, iron metabolism and skeletal muscle function. Furthermore, we study primary hepatocytes treated with FGF23 or Pi to examine activation of downstream signaling events & expression levels of specific target genes. We determine if co-treatment with inhibitors of Pi uptake & of downstream mediators block these observed effects.
Results
A 3% Pi diet as well as an adenine-rich diet promote inflammation, iron dysregulation & skeletal muscle wasting in mice. Outcomes are not alleviated in FGFR4 knockout mice. Furthermore, liver Pi accumulation occurs before hyperphosphatemia, as shown by 2% Pi diet. In cultured hepatocytes, inflammatory cytokine and hepcidin expression are induced by Pi in a dose-dependent manner. Moreover, Pi activates NFkB signaling. Blocking Pi uptake & NFkB attenuates the observed Pi-induced effects.
Conclusion
We postulate in CKD, gradual elevations in serum Pi as well as tissue Pi accumulation, which may occur before detectable changes in systemic Pi, promotes inflammation & anemia by targeting the liver to induce gene programs that regulate inflammatory responses & iron metabolism. In turn, these events promote muscle wasting. Our study indicates these Pi effects may be FGF23-independent. Pharmacological approaches targeting Pi uptake and excretion or Pi’s direct hepatic actions may alleviate various CKD-associated pathologies.
Funding
- NIDDK Support