High Phosphate Diets Drive Hypertension by Hijacking Brain Growth Factor Signaling

Inorganic phosphate is ubiquitous in processed foods as a preservative and flavor enhancer, pushing average dietary intake well above recommended daily allowances. While high phosphate has long been known to harm cardiovascular health in chronic kidney disease patients, its mechanisms in the general population have been poorly understood. This study, published in Circulation, uncovers a previously unrecognized brain-centered pathway connecting excess phosphate consumption to hypertension and sympathetic nervous system dysregulation.

Using male Sprague-Dawley rats fed either a normal phosphate diet (NP, 0.6%) or a high phosphate diet (HP, 1.2%) for 12 weeks, researchers demonstrated that HP animals developed elevated mean arterial pressure and an exaggerated exercise pressor reflex (EPR) — the cardiovascular response to contracting skeletal muscle. The HP diet significantly raised serum FGF23 (15.3 vs. 8.9 pM) and, critically, cerebrospinal fluid FGF23 (8.3 vs. 7.2 pM), with a significant positive correlation between the two. FGF23 protein was elevated in the brainstem and cerebral cortex, but not the hippocampus, of HP animals.

To establish that circulating FGF23 can physically enter the brain, infrared-labeled FGF23 was injected intravenously and tracked by fluorescent microscopy. It appeared in the choroid plexus, medulla oblongata, nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and caudal ventrolateral medulla (CVLM) — all key autonomic cardiovascular control centers — even at doses 100-fold lower than the standard tracer dose. A control protein of similar molecular weight (osteopontin) did not appear in these regions, ruling out nonspecific leakage.

Intracerebroventricular (ICV) injection of PD173074, a pan-FGFR1–4 inhibitor, dramatically attenuated the exaggerated renal sympathetic nerve activity (RSNA) and MAP responses to muscle contraction in HP rats (ΔRSNA reduced from 84±53% to 32±25%; ΔMAP from 35±14 to 9±7 mmHg), without affecting NP animals. Strikingly, peripheral IV injection of the same inhibitor had no effect, confirming the effect is central. ICV administration of BLU9931, a relatively selective FGFR4 inhibitor, replicated these results in HP rats only. In contrast, AZD4547 (FGFR1–3 inhibitor) and a C-terminal FGF23 peptide that blocks α-Klotho-dependent signaling had no significant effect in either group, pointing specifically to FGFR4 — which signals independent of α-Klotho — as the critical mediator.

These results establish a novel pathophysiologic paradigm: dietary phosphate overload → elevated circulating FGF23 → FGF23 crossing the blood-brain barrier → brainstem FGFR4 activation → sympathetic overactivation and hypertension. This pathway is separate from classical peripheral FGF23/α-Klotho signaling in the kidney and heart, representing a distinct central mechanism of phosphate-induced cardiovascular harm.