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Dynamic single cell transcriptomics defines kidney FGF23/KL bioactivity and novel segment-specific inflammatory
Rafiou Agoro1, Jered Myslinski2, Yamil G Marambio3
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA; The Jackson Laboratory, Bar Harbor, Maine, USA.
Kidney International
|January 19, 2025
Summary
Fibroblast growth factor 23 (FGF23) signaling in the kidney is detailed at single-cell resolution. FGF23 actions depend on αKlotho (KL) and influence phosphate metabolism via MAPK and vitamin D pathways.
Area of Science:
- Nephrology
- Molecular Biology
- Genomics
Background:
- Fibroblast growth factor 23 (FGF23) and its coreceptor αKlotho (KL) are crucial for phosphate metabolism.
- Dysregulation of FGF23/KL signaling is implicated in various kidney diseases.
- The precise spatial-temporal mechanisms of FGF23 action in the kidney are not fully understood.
Purpose of the Study:
- To elucidate the single-cell resolution mechanisms of kidney FGF23 bioactivity.
- To identify specific cell types and pathways regulated by FGF23 in vivo.
- To uncover novel FGF23-dependent signaling crosstalk.
Main Methods:
- Single-cell RNA sequencing (scRNAseq) of mouse kidneys after FGF23 injection.
- Computational analysis of cell clusters and differential gene expression.
- Integration of ATACseq and RNAseq data from a KL-expressing cell line.
- In vitro and in vivo validation of identified pathways.
Main Results:
- FGF23 bioactivity was mapped to specific epithelial, endothelial, stromal, and immune cell populations.
- KL expression in proximal tubules and distal convoluted tubules is critical for FGF23 action.
- Temporal FGF23 responses modulated MAPK signaling and vitamin D metabolism via distinct transcriptional regulons.
- Unexpected crosstalk between FGF23-MAPK and TNF receptor/NF-κB signaling was identified, inhibiting FGF23 bioactivity.
Conclusions:
- Novel FGF23-dependent pathways were uncovered at the single-cell level in the kidney.
- These findings provide insights into FGF23-related kidney diseases.
- Understanding these mechanisms may aid in developing targeted therapeutic strategies.
