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Transcriptomics profiling reveals novel FGF23 targets in a Klotho-dependent and independent manner

ABSTRACT: Bone-derived hormone FGF23 and its co-receptor Klotho form a trimeric complex with FGFRs in target tissues, thus governing physiological FGF23 actions. Prolonged excess FGF23 levels in conditions like chronic kidney disease (CKD) may have cardiotoxic and inflammatory effects without requiring Klotho as a coreceptor. If and how FGF23 functions independently of Klotho is a topic of significant interest. Using in-vitro transcriptomics and further bioinformatics analysis, here we show that transient-low FGF23 treatment (~physiological) in presence of Klotho exhibit canonical signaling. However lack of Klotho led to almost no change in transcriptomics after FGF23 treatment. On the other hand, prolonged-excess FGF23 treatment (~pathological) revealed many novels targets of FGF23, which are also emerging biomarkers of CKD, suggesting FGF23 may activate these molecules in CKD. Remarkably, Klotho acted as a molecular switch by regulating, together with FGF23, the above-mentioned transcripts, thus determining the fate of FGF23 signaling. Overall, our findings provide proof-of-principle evidence for the Klotho dependent and independent FGF23 actions, which may hold great potential for investigating a precise role of FGF23 in health and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248734 | GEO | 2023/12/06

REPOSITORIES: GEO

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Transcription profiling of mouse kidney from FGF23, TG and WT mice

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2008-06-15 | E-GEOD-6979 | biostudies-arrayexpress

Gene expression analysis of Kidneys from FGF23 TG and WT mice

Project description:Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes renal inorganic phosphate (Pi) wasting by down-regulation of sodium phosphate co-transporter 2a (Npt2a). The mechanism behind this action is unknown. We have previously generated transgenic mice (TG) expressing human wild-type FGF23 under the control of the α1 (I) collagen promoter. In this study we performed a large scale gene expression study of kidneys from TG mice and wild-type littermates. Several genes that play a role in Pi regulation had decreased expression levels, such as Npt2a, but also Pdzk1 which is a scaffolding protein known to interact with NPT2a. Importantly, the Klotho gene, a suggested crucial co-factor for FGF23 receptor binding and activation, was the most affected decreased gene. However, other genes proposed to regulate Pi levels, such as secreted Frizzled Related Protein 4 (sFRP4), Na+/H+ exchanger regulatory factor 1 (NHERF1) and the FGF-receptors 1-4, revealed no changes. Interestingly, expression levels of inflammatory response genes were increased and histological analysis revealed tubular nephropathy in the TG mice kidneys. In conclusion, FGF23 TG mice have altered kidney gene expression levels of several genes thought to be part of Pi homeostasis and an increase in inflammatory response genes, data supported by histological analysis. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation. Keywords: Genetic Modification

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Deletion of Klotho enhancer deepens sexual dimorphism of gene expression without impacting female resistance to kidney injury [ChIP]

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