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Fig. 1 | Molecular and Cellular Pediatrics

Fig. 1

From: How FGF23 shapes multiple organs in chronic kidney disease

Fig. 1

Regulators of FGF23 in CKD. a Fibroblast growth factor (FGF) 23 is expressed and secreted in the bone by osteocytes and osteoblasts. b In CKD, enhanced parathyroid hormone (PTH) levels stimulate the transcription of FGF23 by binding to PTH 1 receptor (PTH1R) activating protein kinase A (PKA)/nuclear receptor related-1 (Nurr1) signaling pathway. In addition, PTH-mediated PKA activation inhibits sclerostin that leads to induction of the Wnt pathway following FGF23 mRNA expression. Treatment with 1,25-dihydroxy vitamin D (1,25OHD) in CKD patients upregulates FGF23 transcription via binding to vitamin D receptor (VDR)/retinoid X receptor (RXR) heterodimer complex that translocates into the nucleus and activates vitamin D response elements (VDRE) in the FGF23 gene. Furthermore, FGF23 transcription is stimulated by calcium-dependent nuclear factor of activated T cells (NFAT) signaling pathway leading to induction of NFAT response elements in the FGF23 promotor. High phosphate induces polypeptide n-acetylgalactosaminyltransferase 3 (GalNt3), thereby stabilizing intact FGF23 (iFGF23) protein on the post-translational level. Iron deficiency and inflammation stabilize hypoxia-inducible factor 1 α (HIF1α) that bind to HIF-binding sites in the FGF23 promotor stimulating its transcriptional activity. Moreover, HIF1α mediates the cleavage of FGF23 protein through erythropoietin (EPO), while EPO itself enhances FGF23 transcription. The increase in CKD-related inflammatory factors stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) mediating FGF23 transcription through Orai1 activation. Created with BioRender.com

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