Abstract: TH-PO0787
High Phosphate-Induced Hypertension Is Mediated by Central Nervous System (CNS) Translocation of Fibroblast Growth Factor 23 and Occurs via Fibroblast Growth Factor Receptor 4 (FGFR4)-Dependent, Clathrin-Mediated Endocytosis with Partial Klotho Independence
Session Information
- CKM Axis: Vascular Dysfunction, Atherosclerosis, and Heart Failure in Kidney Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Carroll, Isabelle J., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Pastor, Johanne, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Moe, Orson W., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background
High phosphate (HP) intake is associated with hypertension via activation of the sympathetic nervous system, but the mediating mechanisms linking circulating fibroblast growth factor 23 (FGF23) to sympathetic outflow from the CNS remains unclear. While FGF23 classically requires Klotho for receptor activation in peripheral tissues to promote phosphaturia, its role in CNS signaling, CNS entry, or cellular uptake are Klotho-dependent remains unknown.
Methods
Rats were fed a HP diet (1.2%) for 12 weeks. Serum, CSF, and brain tissues were collected. FGF23 distribution in the CNS was assessed by immunoblot (IB) and IHC. CNS translocation was evaluated using intravenously administered infrared-labeled FGF23 (IR-FGF23).
In vitro uptake studies were performed in HeLa and human choroid plexus (ChP) epithelial cells expressing native FGFRs with or without Klotho transfection. Subcellular localization, receptor colocalization, and uptake mechanisms were assessed by confocal microscopy and IB. Surface-bound versus internalized FGF23 was distinguished using acid wash assays.
Results
FGF23 levels were increased in plasma, CSF, and brain tissue in HP animals. FGF23 localized prominently to the ChP and brainstem cardiovascular regulatory regions, consistent with CNS entry, and colocalized with FGFR4 and Klotho in vivo.
In vitro, IR-FGF23 uptake colocalized with FGFR4 in both cell models, supporting receptor-associated internalization. Klotho overexpression in both cell models increased global FGF23 uptake; however, cellular uptake was observed in Klotho-negative cells, indicating that Klotho enhances but is not required for cellular uptake.
FGF23 colocalized with clathrin, demonstrating uptake via a clathrin-mediated endocytic pathway and persisted in the absence of Klotho, indicating a Klotho-independent endocytic mechanism. Acid wash experiments confirmed intracellular retention of FGF23 and reflected both membrane-bound and internalized pools.
Conclusion
FGF23 undergoes CNS translocation and cellular uptake via FGFR4-dependent, clathrin-mediated endocytosis that is augmented, but not strictly gated by Klotho. These findings redefine CNS FGF23 signaling as a receptor-mediated trafficking process with partial Klotho independence and establish a mechanistic framework for FGF23-mediated neurohumoral regulation in high phosphate states.