High Phosphate-Induced Hypertension and Sympathetic Nervous System Overstimulation Is Mediated by Peripheral Fibroblast Growth Factor 23 Translocation into the Central Nervous System, Fibroblast Growth Factor Receptor 4 (FGFR4) Activation, and Recept

Background: Recent research links high phosphate (P) intake to hypertension via activation of the sympathetic nervous system, but the mediating mechanisms remain elusive. P ingestion prompts the release of fibroblast growth factor 23 (FGF23) from osteocytes to induce adaptive phosphaturia and while known to facilitate many important homeostatic effectors renally, the presence of FGF23 protein and its receptors (FGFRs) in the central nervous system (CNS) and their role in blood pressure (BP) regulation during high P intake remain elusive. And while Klotho functions as a FGFR coreceptor for FGF23 action renally, its mediating role in the CNS is unknown. Methods: Renal sympathetic nerve activity (RSNA) and BP were assessed in normal-P (NP) and high P-treated (HP) rats under anesthesia and after decerebration. FGF23 protein in the CNS was measured by immunoblot (IB) and immunohistochemistry (IHC). CNS FGF23 translocation was measured using IR-FGF23 injected intravenously (IV). FGF23 activity blockade was by intracerebroventricular (ICV) injection of FGFR inhibitors. Cellular uptake was measured in cell models expressing native FGFRs and transiently transfected with Klotho. Results: Compared to NP, HP rats showed elevated resting mean ABP and elevated FGF23 protein in peripheral blood, CSF, and in brain tissue. Peripheral IV injection of IR-FGF23 yielded robust IR signals in ChP and regions of the brainstem known to regulate BP, including medulla oblongata, nucleus of the solitary tract, and rostral ventrolateral medulla, while IB showed elevation in the cerebral cortex and brainstem. In IHC, IR-FGF23 colocalized with native FGFR4 and Klotho in ChP. The HP-induced sympathetic overactivation and hypertensive effects were attenuated by ICV administration of Pan-FGFR and FGFR4 inhibitors and not by FGFR1-3 or FGF23 C-term peptide. Cellular uptake of IR-FGF23 was mediated by transfected Klotho in cultured human choroid plexus and HeLa cells. Conclusion: The hypertensive effects of HP at rest and during simulated exercise are mediated by the translocation of circulating FGF23 across the blood-CSF barrier and acts on a Klotho-FGFR4-dependent manner leading to exaggerated sympathetic outflow, mediating elevated BP during muscle contraction.