High Phosphate-Induced Hypertension Is Mediated by Peripheral Fibroblast Growth Factor 23 Translocation into the Central Nervous System, Fibroblast Growth Factor Receptor Activation, and Sympathetic Nervous System Stimulation

Background: Recent research links high phosphate (P) intake to hypertension via activation of the sympathetic nervous system, but the intermediate mechanisms are unknown. P-rich diets prompt the release of fibroblast growth factor 23 (FGF23) from bone cells to promote negative P balance. In the kidney, FGF23 inhibits P reabsorption and vitamin D activation. Although FGF23 protein and its receptors are known to be present in the central nervous system (CNS), their function and specifically their role in blood pressure regulation during high P intake remain elusive. Methods: Morphometric features and renal sympathetic nerve activity (RSNA) body weight and organ-body weight ratios 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 immunoblots (IB) and immunochemistry (IHC). FGF23 translocation into the brain was measured by infrared (IR) labelled FGF23 injected intravenously. FGF23 activity blockade was achieved by intracerebroventricular injection of FGFR inhibitors. Results: Resting mean arterial pressure was higher in HP rats compared to NP rats (P<0.01). FGF23 protein was higher in peripheral blood, cerebrospinal fluid (CSF) and brain tissue in HP rats. IHC revealed FGF23 in choroid plexus and areas of the brainstem, and IB showed higher FGF23 in the hippocampus and brainstem but not cerebral cortex. Injection of IR-FGF23 showed robust signals in choroid plexus, and parts of the brain stem. The HP-induced hypertensive effects were blocked by pharmacologic inhibition of FGFR by broad spectrum and FGFR4 inhibitors injected intracerebroventricularly; and not by the FGF23 C-terminal peptide. FGFR4 inhibition in the CNS reduced HP-induced sympathetic nervous system activation. Conclusion: We conclude that the hypertensive effects of HP during simulated exercise are mediated by the translocation of circulating FGF23 across the blood/CSF barrier (BCSFB) and occurs independently of the canonical FGF23 pathway leading to exaggerated sympathetic outflow and elevated blood pressure during muscle contraction.