Abstract: SA-PO232
Renal Regulation of Fibroblast Growth Factor 23 Expression in Response to Inflammation Is Mediated by a Unique Genomic Mechanism
Session Information
- CKD-MBD: Basic and Translational
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Lee, Seong Min, University of Wisconsin-Madison Department of Nutritional Sciences, Madison, Wisconsin, United States
- Meyer, Mark B., University of Wisconsin-Madison Department of Nutritional Sciences, Madison, Wisconsin, United States
- Pike, J. Wesley, University of Wisconsin-Madison Department of Biochemistry, Madison, Wisconsin, United States
Background
Fibroblast growth factor 23 (FGF23) is a peptide hormone produced in bone to control phosphate homeostasis and vitamin D metabolism in the kidney. FGF23 is inappropriately upregulated in many tissues in response to inflammation and disease, potentially causing phosphate wasting and bone disorders. To model inflammation, we have shown that lipopolysaccharides (LPS) increased serum intact FGF23 (iFGF23) production in vivo via genomic mechanisms mediated by two distinct enhancers at -16 kb upstream and a large 4 kb proximal enhancer (PE) near the gene TSS in multiple tissues. However, the kidney LPS response is only in PE.
Methods
In this study, we generated 9 mouse strains to dissect the PE enhancer to examine the tissue specific regulation of LPS-induced Fgf23. Deletions were introduced by CRISPR/Cas9 editing in C57BL/6J mice and the levels of tissue Fgf23 mRNA and serum iFGF23 in the mutants were compared with controls after LPS treatment for 6 h. ChIP-seq was performed in kidneys from wildtype mice for inflammatory factors after LPS treatment for 1 h.
Results
The results showed that while the induction in bone marrow, thymus, lung, and intestine was mediated by one region (PE1), a second, independent region (PE2) was responsible for renal Fgf23 induction. Fgf23 induction by LPS in bone, liver, and spleen was mediated by both regions (PE1 and PE2). Both PE1 and PE2 were further subdivided to explore mechanisms for Fgf23 induction in the kidney where inflammation occurs under pathological conditions, such as chronic kidney disease. With these deletions, LPS-treated mice were resistant to Fgf23 mRNA increases in the kidney, whereas the skeletal response remained. We confirmed complete loss of LPS-mediated Fgf23 increases in both kidney and bone with a double knockout of the -16 kb region and PE together (DKO). Serum iFGF23 levels were unchanged in the DKO with LPS treatment. Following LPS treatment, ChIP-seq analysis showed increased binding of STAT3, p65, and p50 at these same regions in the kidney.
Conclusion
In conclusion, we have discovered that the regulation of FGF23 production in response to inflammation is orchestrated by a renal-specific enhancer. This leads to a unique mechanism by which tissues produce Fgf23 and increase iFGF23 that modulates vitamin D metabolism and phosphate handling in disease.
Funding
- NIDDK Support