Background: Recent studies have highlighted the deleterious role of high phosphate intake in hypertension by means of sympathetic overactivation, yet the underlying mechanisms remain unclear. Dietary phosphate loading triggers physiologic release of FGF23 (fibroblast growth factor-23) from the bone to maintain phosphate homeostasis. Both FGF23 and FGF receptors (FGFRs) are present in the central nervous system, but their role in neural control of blood pressure during phosphate loading is unknown. We investigated central FGF23/FGFR signaling in high-phosphate diet-induced sympathetic dysregulation of blood pressure in rats.
Methods: FGF23 protein levels were measured by immunoprecipitation, immunoblotting, and immunohistochemistry. FGF23 translocation into the brain was determined by injecting infrared-labeled FGF23 intravenously into anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction were measured in decerebrate Sprague-Dawley rats treated with either a normal 0.6% phosphate diet (NP) or a high 1.2% phosphate diet (HP) for 12 weeks before and after intracerebroventricular (ICV) administration of FGFR signaling inhibitors.
Results: Excess phosphate intake significantly increased FGF23 protein levels in the brainstem (HP versus NP, P=0.009) and cerebrospinal fluid (HP versus NP, P<0.001). Peripheral injection of infrared-labeled FGF23 showed clear entry into the choroid plexus and medulla oblongata. ICV administration of PD173074, a pan-FGFR(1-4) inhibitor, significantly attenuated the heightened RSNA (Δ=84±53 versus 32±25% [P<0.0001]) and MAP (Δ=35±14 versus 9±7 mm Hg [P<0.0001]) responses to muscle contraction in HP animals, but did not affect the RSNA and MAP responses during stimulation in NP animals (ΔRSNA=40±29 versus 30±22% and ΔMAP=18±13 versus 13±9 mm Hg before versus after ICV injection). ICV injection of BLU9931, a relatively selective FGFR4 inhibitor, also decreased the responses in HP rats only (∆RSNA=112±70 versus 65±46% [P=0.006] and ∆MAP=41±14 versus 20±14 mm Hg [P<0.0001] before versus after ICV injection). However, ICV administration of AZD4547, a FGFR1-3 inhibitor, and C-terminal FGF23 peptide, a competitive inhibitor of FGF23/FGFR/α-Klotho complex formation, did not alter the responses in either NP or HP animals.
Conclusions: Our data reveal a novel pathophysiologic paradigm of high-phosphate diet-induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting through FGFR4.
Keywords: blood pressure; phosphates; receptors, fibroblast growth factor.