Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-17
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IF 8.9
Wang Jing,Li Zuo-Lin,Zhou Yan,Li Zhong-Tang,Tu Yan,Hu Xin-Hui,Zhu Jin-Hua,Liu Bi-Cheng,Liu Hong
Background Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) represents a novel therapeutic approach for renal anemia, a prevalent complication of chronic kidney disease (CKD). However, the effects of HIF-PHI on renal functional outcomes remain poorly characterized. Here, the potential effects of FG-4592, an orally administered HIF-PHI, on renal fibrosis were explored systematically. Methods In this study, a CKD rat model was established through subtotal 5/6 nephrectomy. Rats were administered either FG-4592 or vehicle control via oral gavage three times weekly for 12 consecutive weeks. Additionally, recombinant FGF23 was continuously delivered via subcutaneously implanted Alzet osmotic minipumps for 28 days. Results Interestingly, we found that CKD-induced anemia was significantly ameliorated in CKD rats with FG-4592 treatment. Meanwhile, markedly alleviated histopathological changes and renal tubulointerstitial fibrosis (TIF) were observed in rats with FG-4592 administration. Notably, serum levels of intact FGF23 (iFGF23) were significantly reduced following FG-4592 administration in CKD rats. This finding was subsequently validated in CKD patients receiving Roxadustat therapy. Mechanistically, we illustrated that inhibition of the iFGF23-WNT5A pathway was the exact mechanism by which FG-4592 ameliorated TIF. Further, we also demonstrated that transcriptional activation of Furin enzyme was the exact molecular mechanism for FG-4592-mediated iFGF23 cleavage. Conclusions FG-4592 attenuates TIF through Furin-mediated proteolytic cleavage of iFGF23. These findings provide novel mechanistic insights into HIF-PHI-mediated renal protection and establish a theoretical framework for clinical translation.
研究领域:
肾脏病学
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分子生物学
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DOI
PubMed
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Endocrine Metabolic & Immune Disorders-Drug Targets
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2026
·Vol. 26
·期 1
·E18715303420913
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IF 2
Jiawei Cao,Yuewen Tang,Feng Wan,Tingjiao Xu,Ruchun Yang
Introduction In this study, we aim to investigate the mechanism by which extracellular phosphate (Pi) regulates the transcription of fibroblast growth factor 23 (FGF23) in osteoblasts and the effects of celastrol on FGF23 expression in UMR-106 cells and in chronic kidney disease (CKD) rat models. Methods We used Pi to induce FGF23 expression in a rat osteoblastic cell line as a model and then treated the cells with celastrol. The cytotoxicity of Pi and celastrol was assessed using the CCK-8 assay. FGF23 expression was measured using real-time quantitative PCR (RT-qPCR), and its promoter activity was evaluated using luciferase reporter assays. To detect active signal transducer and activator of transcription 3 (STAT3), immunofluorescence and Western blotting were performed. The 5/6 nephrectomized rat model was established to investigate the effects of celastrol on FGF23 expression in vivo. An enzyme-linked immunosorbent assay was carried out to examine serum FGF23 levels in rats. RT-qPCR detected the mRNA levels of FGF23 and STAT3 in the femurs of CKD rats. Results We found that high Pi activated STAT3 and promoted its nuclear translocation, leading to elevated FGF23 expression, which was suppressed by celastrol. Additionally, in rats subjected to 5/6 nephrectomy with high serum Pi levels, serum FGF23 levels and skeletal STAT3 expression were significantly decreased after celastrol treatment. Discussion Therefore, celastrol could have therapeutic effects on CKD by decreasing serum FGF23. Conclusion High Pi activates STAT3 and induces FGF23 expression. Furthermore, celastrol can attenuate increased FGF23 expression induced by high Pi, potentially via inhibition of STAT3 activation.
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Journal of Functional Foods
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2026
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IF 3.9
Lu Wang,Kejian Wei,Jiahua Yan,Kun Wang,Siqi Liu,Fei Fang,Yu Jiang
As a major citrus flavonoid, hesperidin (HP) shows bone-protective potential, yet its role in calcium–phosphorus homeostasis and antioxidant mechanisms remains unclear. This study investigated the anti-osteoporotic effects of HP in retinoic acid (RA)-induced osteoporotic mice and primary bone marrow mesenchymal stem cells (BMSCs). HP promoted BMSC proliferation, migration, and osteogenic differentiation, with increased alkaline phosphatase (ALP) activity and mineralization. Network pharmacology identified antioxidant PI3K/AKT/FOXO1 pathways as key targets, with fibroblast growth factor 23 (FGF23) as a pivotal effector. In osteoporotic mice, HP normalized serum calcium, phosphorus, and 25-hydroxyvitamin D, increased bone formation and decreased resorption markers, alleviating bone loss and preserving trabecular microarchitecture and enhancing biomechanical properties. Mechanistically, PI3K/AKT/FOXO1-mediated FGF23 suppression was essential for osteoprotection, as confirmed using a PI3K inhibitor. Collectively, these findings suggest that HP ameliorates RA-induced osteoporosis by restoring calcium–phosphorus homeostasis via PI3K/AKT/FOXO1-dependent FGF23 inhibition, underscoring its potential as a functional food ingredient.
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Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Yingying Cai,Jiali Hu,Mingjie He
Materials and Methods LOAD rats and A β microglia were constructed by using A β 1-40 and IBO mixture. The effect of KL-FGF23-VD axis on LOAD was investigated by transfecting overexpressing and interfering with KL gene adenovirus, and IKK-16 was added to A β microglia to explore the effect of KL-FGF23-VD axis on regulation of IKK/NF- κ B signaling pathway. Results The results showed that, in KL-OE group, FGF23 was decreased in the hippocampus of LOAD rats compared with control and KL-si, and the trend was opposite in the KL-si group. The KL-FGF23-VD axis can alleviate inflammatory response, reduce the deposition of A β , and inhibit activation of the NF- κ B pathway and neuron apoptosis in brain tissue of LOAD rats. In A β microglia, the expression of KL-FGF23-VD axis was consistent with animal experiments. The KL-FGF23-VD axis can inhibit the expression of A β microglia inflammatory factors and the activation of microglia and NF- κ B pathway. Meanwhile, IKK expression was decreased in KL-OE group compared with KL-si and Control. In the IKK-16 addition group, the ability of KL-FGF23-VD axis to inhibit the activation of microglia and NF- κ B pathway was enhanced. Conclusions These findings suggest a potential role of the KL-FGF23-VD axis in AD treatment by regulating the IKK/NF- κ B pathway.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
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POULTRY SCIENCE
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2022
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IF 4.014
Zhengtian Lyu,Haifang Li,Xin Li,Hui Wang,Hongchao Jiao,Xiaojuan Wang,Jingpeng Zhao,Hai Lin
ABSTRACT Fibroblast growth factor 23 ( FGF23 ), a bone-derived hormone, is involved in the reabsorption of phosphate ( P ) and the production of vitamin D hormones in the kidney. However, whether and how FGF23 regulates chicken bone metabolism remains largely unknown. In the present study, we investigated the effect of FGF23 on osteogenic differentiation and mineralization of chicken bone marrow mesenchymal stem cells ( BMSCs ). First, we found that the transcription of FGF23 was inhibited by β-glycerophosphate sodium ( GPS , 5 mM, 10 mM, 20 mM) and 10 −9 M 1, 25-dihydroxyvitamin D3 ( 1, 25(OH) 2 D 3 ), but was stimulated by 10 −7 M 1, 25(OH) 2 D 3 and parathyroid hormone ( PTH , 10 −9 M, 10 −8 M, 10 −7 M). Second, overexpression of FGF23 by the FGF23 adenovirus ( Adv-FGF23 ) suppressed the formation of mineralized nodules ( P < 0.001) and alkaline phosphatase ( ALP ) activity ( P < 0.05) in both differentiated and mineralized osteoblasts. Administration of FGF receptor 3 ( FGFR3 ) inhibitor (50 nM) was sufficient to restore the FGF23-decreased ALP activity ( P < 0.05), but not for the formation of mineralized nodules. In addition, the phosphorylation of ERK increased considerably with Adv-FGF23 overexpression ( P < 0.05). Administration of an ERK-specific inhibitor (10 μM) could down-regulate the phosphorylation of ERK ( P-ERK ) ( P < 0.05) and slightly restored the Adv-FGF23-reduction of ALP activity ( P = 0.08). In summary, our data suggest that GPS, 1, 25(OH) 2 D 3 , and PTH could regulate FGF23 mRNA expression in vitro. FGF23 is a negative regulator of bone remodeling. FGF23 not only inhibits BMSCs osteogenesis through the FGFR3-ERK signaling pathway but also suppresses the mineralization of mature osteoblasts.
研究领域:
骨生物学
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细胞生物学
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分子生物学
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内分泌学
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PubMed
高影响因子
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