High-salt diet modulates endocrine regulation between cortisol and FGF23

Excessive dietary salt intake is a global health concern, affecting cardiovascular, renal, and bone health. While the renin-angiotensin-aldosterone system (RAAS) is a known regulator of dietary salt-induced hormonal responses, the impact of adrenal cortisol remains unclear. Here, we performed a retrospective analysis in individuals (n=292) consuming a random diet. Dietary salt intake positively correlated with urinary cortisol and inversely correlated with plasma fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D homeostasis. Controlled salt diets in healthy individuals confirmed a dose-dependent increase in urinary cortisol and suppression of plasma FGF23. In mice, oral corticosterone, a cortisol analogue, reduced circulating FGF23 levels. RNA-seq analysis of corticosterone-treated MC3T3 osteoblasts identified suppression of FGF23 via glucocorticoid receptor activation, anti-inflammatory pathways, and reduced osteoblast activity. Our findings reveal a novel endocrine cascade where high salt intake elevates cortisol and suppresses FGF23, with potential implications for bone, kidney, and cardiovascular health. SIGNIFICANCE STATEMENTExcessive dietary salt intake is a global health concern with poorly understood hormonal consequences beyond the renin-angiotensin-aldosterone system. Here, we identify a novel endocrine cascade in which high salt intake elevates cortisol signaling and suppresses fibroblast growth factor 23 (FGF23), a bone-derived hormone central to phosphate and vitamin D homeostasis. These findings are supported by a human cohort on random diets, a controlled dietary salt intervention, and corticosterone experiments in mice and osteoblasts. Mechanistically, cortisol suppresses FGF23 via glucocorticoid receptor activation, anti-inflammatory signaling, and repression of osteoblast activity. These findings have potential implications for bone, kidney, and cardiovascular health, and suggest that dietary salt intake may influence the clinical interpretation of cortisol and FGF23 measurements.