Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation, CIRCULATIONAHA.124.071605. https://doi.org/10.1161/CIRCULATIONAHA.124.071605 Dr. Han-Kyul Kim et al.
Points
- This study investigated how high dietary phosphate causes hypertension using a rat model fed a high-phosphate diet for twelve weeks to induce sympathetic overactivation and elevated blood pressure.
- The results demonstrated that excess dietary phosphate significantly increased levels of the hormone FGF23 in the brainstem and cerebrospinal fluid, showing it crosses the blood-brain barrier.
- Central administration of a pan-fibroblast growth factor receptor inhibitor successfully blunted the exaggerated blood pressure and sympathetic nerve activity responses observed in the high-phosphate diet group during stress.
- A selective inhibitor for fibroblast growth factor receptor 4 similarly reduced hypertension, whereas inhibitors for FGFR1-3 had no effect, indicating FGFR4’s specific role in this pathway.
- These findings establish a novel pathophysiological mechanism where central FGFR4 signaling mediates phosphate-induced hypertension, identifying this receptor as a promising new therapeutic target for future treatment strategies.
Summary
This research investigated the central nervous system mechanisms by which high dietary phosphate intake contributes to the development of hypertension. While the deleterious role of excess phosphate in sympathetic overactivation is recognized, the underlying pathways have been unclear. This study evaluated the hypothesis that fibroblast growth factor–23 (FGF23), released from bone in response to phosphate loading, acts centrally to mediate these effects. Researchers utilized a decerebrate Sprague-Dawley rat model, comparing animals on a high-phosphate (1.2%) diet (HP) for 12 weeks to those on a normal-phosphate (0.6%) diet (NP). The study aimed to determine if FGF23 crosses the blood-brain barrier and if central fibroblast growth factor receptor (FGFR) signaling is essential for phosphate-induced sympathoexcitation.
The results demonstrated that the HP diet significantly increased FGF23 protein levels in the brainstem (P = 0.009) and cerebrospinal fluid (P < 0.001) compared to the NP diet. Intravenously injected labeled FGF23 was shown to enter the medulla oblongata. During simulated exercise via muscle contraction, HP rats exhibited exaggerated responses that were attenuated by central FGFR inhibition. Intracerebroventricular administration of a pan-FGFR inhibitor, PD173074, significantly reduced the heightened renal sympathetic nerve activity (RSNA) response (Δ=84±53% vs. 32±25%, P<0.0001) and mean arterial pressure (MAP) response (Δ=35±14 vs. 9±7 mm Hg, P<0.0001) in HP animals. Similarly, a selective FGFR4 inhibitor, BLU9931, also blunted these responses (ΔRSNA: 112±70% vs. 65±46%, P=0.006; ΔMAP: 41±14 vs. 20±14 mm Hg, P<0.0001), while showing no effect in NP animals.
These findings support a novel pathophysiological paradigm where high dietary phosphate induces hypertension through a central mechanism. The data indicate that FGF23 crosses the blood-brain barrier and acts on central FGFR4, independent of FGFR1–3 or the canonical α-Klotho co-receptor, to drive sympathetic overactivation and increase blood pressure. Inhibitors of FGFR1-3 (AZD4547) and the FGF23/α-Klotho complex did not alter the hypertensive responses in either group. This research identifies central FGFR4 signaling as a specific and potentially valuable therapeutic target for managing hypertension driven by the high phosphate content common in processed foods. No hazard ratios or confidence intervals were provided in the original abstract.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.071605
References Kim, H.-K., Fukazawa, A., Smith, S. A., Mizuno, M., Rothermel, B. A., Fujikawa, T., Galvan, M., Gautron, L., Pastor, J. V., Carroll, I., Moe, O. W., & Vongpatanasin, W. (2025). High dietary phosphate intake induces hypertension and sympathetic overactivation through central fibroblast growth factor receptor signaling. Circulation, CIRCULATIONAHA.124.071605. https://doi.org/10.1161/CIRCULATIONAHA.124.071605
