Transcriptomics profiling reveals novel FGF23 targets in a Klotho-dependent and independent manner
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ABSTRACT:
PROVIDER: PRJNA1045679 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26961600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26961600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26961601_1.fastq.gz | Fastqsanger.gz | |||
| SRR26961601_2.fastq.gz | Fastqsanger.gz | |||
| SRR26961602_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2023-12-06 | GSE248734 | GEO
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. Experiment Overall Design: Five kidneys from FGF23 TG mice and five kidneys from WT littermates was used for Affymetrix Genechip analysis. One Genechip was used/animal. Animals were 8 weeks old when kidneys were collected.
2008-06-15 | E-GEOD-6979 | biostudies-arrayexpress
Project description:Memo is a copper-dependent redox enzyme modulating receptor tyrosine kinase signaling by unknown mechanisms (Meira et al., Nat Cell Biol 2004; MacDonald et al., Science Signal 2014). Memo1 deletion causes a phenotype partially resembling Klotho and Fgf23-deficient mice (Haenzi et al., FASEB J 2014; Moor et al., JBMR Plus 2018) and increases renal abundance of Rho-GTPase RhoA but prevents FGF23-dependent renal ERK phosphorylation and Rho-GTPase Rac1 activation (unpublished). To delineate potential effects of Memo’s redox function on FGF23-driven cellular signaling processes, we performed a redox proteomics screen which identified differently oxidized Rho-GTPase chaperone protein ARHGDIA/Rho-GDP dissociation inhibitor 1 (RhoGDI) as an interaction partner of Memo. RhoGDI is regulated by cysteine oxidation and phosphorylation. Here, we investigated the potential interaction between MEMO and RhoGDI by co-incubation of recombinant proteins MEMO and RhoGDI in cell-free environment to assess the Cys79 oxidation state of RhoGDI.
2023-10-24 | PXD022382 | Pride
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
2007-11-29 | GSE6979 | GEO
Project description:FGF23 is a bone-derived hormone that mediates renal phosphate reabsorption and 1,25(OH)2 vitamin D metabolism via its required co-receptor alpha-Klotho (KL). The functional pathways guiding this hormone’s activity in kidney have not been studied extensively, and whether using other factors with overlapping signaling profiles to produce FGF23-like responses is unclear. To map FGF23-related genes, gene array and single-cell RNA sequencing were utilized on wild type mouse kidneys. After identifying Heparin-binding EGF-like growth factor (HBEGF) as an up-regulated gene in response to FGF23 delivery, KL-null and phosphate-deficient diet fed mouse models and in vitro experiments were utilized to further test HBEGF bioactivity in kidney. Gene array demonstrated that HBEGF was significantly up-regulated following FGF23 delivery to wild type (WT) mice. Next, mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of EGR1, and increased CYP24A1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGFR expression in the proximal tubule (PT), and KL expression in PT and distal tubule (DT) segments. In KL-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased EGR1 and CYP24A, and correction of basally-elevated CYP27B1 was observed. In addition, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased CYP27B1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 renal epithelial cells, HBEGF and FGF23 increased CYP24A1 mRNA. Targeting pathways known to be downstream of FGF23 in kidney may help to control renal phosphate handling in diseases of altered FGF23 bioactivity.
2020-10-01 | GSE138992 | GEO
Project description:Memo is a copper-dependent redox enzyme modulating receptor tyrosine kinase signaling by unknown mechanisms (Meira et al., Nat Cell Biol 2004; MacDonald et al., Science Signal 2014). Memo1 deletion causes a phenotype partially resembling Klotho and Fgf23-deficient mice (Haenzi et al., FASEB J 2014; Moor et al., JBMR Plus 2018).
To delineate potential effects of Memo redox function on FGF23-driven cellular signaling processes, we performed a redox proteomics screen in kidney of whole-body Memo-deficient and control mice treated with recombinant FGF23 or vehicle.
2020-11-04 | MSV000086406 | MassIVE
Project description:Sexual dimorphism in kidney injury markers, such as Klotho, is frequently underestimated or disregarded, as most of the preclinical research is done in male animals. Klotho is well-linked to renal health and its deletion in mice results in a severe accelerated aging-like phenotype and premature death. Here, we identified candidate Klotho enhancers and discovered their function using mice carrying deletions in the enhancer loci. Candidate Klotho enhancers were deleted using CRISPR/Cas9 genome editing. Warm ischemia-reperfusion surgery (IRI) was performed bilaterally to induce acute kidney injury and unilaterally in a fibrosis model. Using ChIP-seq and RNA-seq, we analyzed renal chromatin features and gene expression. ELISA and colorimetric assays were used to measure serum FGF23 and serum component levels. Removal of the enhancer caused more substantial reduction in Klotho mRNA levels in female mice compared to males (90 vs. 50%), supported by gene promoter marks remaining more pronounced in males. Weight, lifespan, and fertility of mice lacking the enhancers were not impacted. Only male mutant mice displayed higher Havcr1 expression after IRI than controls (mean 1048 vs. 231.4, p=0.0016). 28 days after unilateral IRI, only males displayed increased fibrosis markers, but with no difference between genotypes. Our findings reveal sexual dimorphism of Klotho gene expression and its enhancer regulation. Only male mutant mice were more susceptible to acute injury and the enhancer deletion had no impact on fibrosis. Additional investigation into the mechanisms governing Klotho regulation is imperative to reassess its effectiveness as a kidney injury marker.
2024-04-04 | GSE243944 | GEO
Project description:α-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of α-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane α-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane α-Klotho isoform. Conclusions: The data presented confirms α-Klotho expression in the kidney tubule and in artery, and provides evidence of α-Klotho expression across organ systems and cell-types that have not previously been described in humans.
2015-10-13 | PXD002775 | Pride
Project description:Sexual dimorphism in kidney injury markers, such as Klotho, is frequently underestimated or disregarded, as most of the preclinical research is done in male animals. Klotho is well-linked to renal health and its deletion in mice results in a severe accelerated aging-like phenotype and premature death. Here, we identified candidate Klotho enhancers and discovered their function using mice carrying deletions in the enhancer loci. Candidate Klotho enhancers were deleted using CRISPR/Cas9 genome editing. Warm ischemia-reperfusion surgery (IRI) was performed bilaterally to induce acute kidney injury and unilaterally in a fibrosis model. Using ChIP-seq and RNA-seq, we analyzed renal chromatin features and gene expression. ELISA and colorimetric assays were used to measure serum FGF23 and serum component levels. Removal of the enhancer caused more substantial reduction in Klotho mRNA levels in female mice compared to males (90 vs. 50%), supported by gene promoter marks remaining more pronounced in males. Weight, lifespan, and fertility of mice lacking the enhancers were not impacted. Only male mutant mice displayed higher Havcr1 expression after IRI than controls (mean 1048 vs. 231.4, p=0.0016). 28 days after unilateral IRI, only males displayed increased fibrosis markers, but with no difference between genotypes. Our findings reveal sexual dimorphism of Klotho gene expression and its enhancer regulation. Only male mutant mice were more susceptible to acute injury and the enhancer deletion had no impact on fibrosis. Additional investigation into the mechanisms governing Klotho regulation is imperative to reassess its effectiveness as a kidney injury marker.
2024-04-04 | GSE255885 | GEO
Project description:Sexual dimorphism in kidney injury markers, such as Klotho, is frequently underestimated or disregarded, as most of the preclinical research is done in male animals. Klotho is well-linked to renal health and its deletion in mice results in a severe accelerated aging-like phenotype and premature death. Here, we identified candidate Klotho enhancers and discovered their function using mice carrying deletions in the enhancer loci. Candidate Klotho enhancers were deleted using CRISPR/Cas9 genome editing. Warm ischemia-reperfusion surgery (IRI) was performed bilaterally to induce acute kidney injury and unilaterally in a fibrosis model. Using ChIP-seq and RNA-seq, we analyzed renal chromatin features and gene expression. ELISA and colorimetric assays were used to measure serum FGF23 and serum component levels. Removal of the enhancer caused more substantial reduction in Klotho mRNA levels in female mice compared to males (90 vs. 50%), supported by gene promoter marks remaining more pronounced in males. Weight, lifespan, and fertility of mice lacking the enhancers were not impacted. Only male mutant mice displayed higher Havcr1 expression after IRI than controls (mean 1048 vs. 231.4, p=0.0016). 28 days after unilateral IRI, only males displayed increased fibrosis markers, but with no difference between genotypes. Our findings reveal sexual dimorphism of Klotho gene expression and its enhancer regulation. Only male mutant mice were more susceptible to acute injury and the enhancer deletion had no impact on fibrosis. Additional investigation into the mechanisms governing Klotho regulation is imperative to reassess its effectiveness as a kidney injury marker.
2024-04-04 | GSE243945 | GEO