# High-Phosphate-Induced Hypertension: The Pathogenic Role of Fibroblast Growth Factor 23 (FGF23) Signaling in Sympathetic Nervous System Activation

## TL;DR

This paper explores how high phosphate intake and FGF23 signaling in the brain contribute to hypertension, especially in conditions like chronic kidney disease.

## Contribution

The paper identifies FGF23's translocation to the brain and FGFR4 signaling as a novel pathogenic mechanism linking high phosphate intake to hypertension.

## Key findings

- Peripheral FGF23 crosses the blood–brain barrier and activates FGFR4-calcineurin signaling, causing sympathetic overactivation.
- High phosphate intake suppresses Klotho, potentially worsening hypertension.
- These mechanisms are relevant to hypertension in chronic kidney disease.

## Abstract

Hypertension remains a major public health concern globally. Accumulating evidence suggests that dietary phosphate (Pi) and fibroblast growth factor 23 (FGF23), a phosphaturic hormone, are involved in blood pressure regulation. Experimental studies have shown that excess Pi consumption, largely from inorganic Pi used as a preservative or flavor enhancer in processed foods, and increased FGF23 may contribute to vascular abnormalities, thereby promoting hypertension. Importantly, recent animal studies have demonstrated that peripheral FGF23 can cross the blood–brain barrier and stimulate FGF receptor 4 (FGFR4)-calcineurin signaling in the brain, contributing to sympathetic overactivation and hypertensive responses during high Pi loading. Additionally, dietary Pi loading leads to suppression of Klotho, which may further contribute to hypertension. Such mechanisms are potentially relevant to chronic kidney disease (CKD), a condition characterized by Pi retention, massively elevated FGF23, sympathetic overactivity, and hypertension. This review highlights current evidence linking Pi-induced FGF23 pathogenically to hypertension, with focus on FGF23 translocation to and FGFR4 signaling in the central nervous system as a potential mechanism and therapeutic target for hypertension associated with high Pi intake and CKD.