Biology subjects

Pathare, G.

Publications and source records attributed to Pathare, G..

3 recordsLinked to original sources

bioRxiv2025

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.

physiology↗

bioRxiv2024

Identification of novel and distinct FGF23 signaling in a Klotho-dependent and -independent manner

Fibroblast growth factor 23 (FGF23) levels are highly elevated in patients with chronic kidney disease (CKD); however, whether it serves merely as a biomarker or actively contributes to kidney inflammation remains unclear. Full-length FGF23 is cleaved into C-terminal FGF23 (cFGF23), which acts as a natural antagonist of FGF23 by inhibiting its binding to the FGF receptor (FGFR) and the co-receptor Klotho. Here, we show that chronically elevated FGF23 levels in a mouse model Hyp-Duk cause sustained-ERK signaling and an inflammatory and immune responses in the kidney. cFGF23, delivered via adeno-associated virus (AAV) gene therapy, successfully mitigated renal sustained-ERK signaling and inflammatory and immune responses in Hyp-Duk mice. On the other hand, acute physiological FGF23 levels in vitro elicited transient-ERK signaling with the expression of canonical early-ERK targets (EGR1, JUNB, FOSB). Consistent with in vivo findings, prolonged pathological FGF23 treatment in-vitro revealed sustained-ERK signaling with upregulation of late-ERK targets (ETV4/5, SPRED1/2, SPRY2/4) and unique inflammatory and immune gene signatures. These effects were significantly mitigated by FGFR and ERK inhibitors, as well as by recombinant cFGF23 treatment. In summary, chronically high levels of FGF23 induce kidney inflammation through the FGFR-Klotho complex and sustained-ERK activation, which are successfully mitigated by cFGF23 gene therapy. TRANSLATIONAL STATEMENTChronically elevated circulating levels of Fibroblast Growth Factor 23 (FGF23) are strongly associated with inflammation and adverse outcomes in chronic kidney disease, but the underlying mechanisms remain poorly understood. Our study identifies sustained activation of the ERK signaling pathway as a key mechanism by which chronic FGF23 elevation induces inflammatory transcriptional programs in the kidney. Importantly, gene therapy using the C-terminal fragment of FGF23 (cFGF23) mitigates these effects, highlighting a potential therapeutic strategy to counteract the excessive FGF23 signaling.

physiology↗

bioRxiv2023

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (low serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that human hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis. SIGNIFICANCE STATEMENTFibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls phosphate and vitamin D metabolism. Excess FGF23 is postulated to cause left ventricular hypertrophy, while FGF23 deficiency reduces life span and mimics age-related diseases in mice. FGF23 is also a potential biomarker for chronic kidney disease and cardiovascular disorders, but its role in disease progression is unclear. Therefore, it is important to explore the regulation of FGF23 production, which is incompletely understood. Our paper identifies extracellular-sodium-NFAT5 signaling as a key regulator of FGF23 formation.

physiology↗