Abstract: SA-PO0279
ETV1 Is a Proximal Tubule-Specific Transcription Factor Controlling Converse Fibroblast Growth Factor 23 (FGF-23) and PTH Regulation of Vitamin D Synthesis
Session Information
- Top Trainee Posters - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 01:00 PM - 01:06 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Solis, Emmanuel, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Jennings, Kayleigh Nicole, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Marambio, Yamil, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Liu, Sheng, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Wan, Jun, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Meyer, Mark B., University of Wisconsin-Madison, Madison, Wisconsin, United States
- White, Kenneth E., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background
1,25(OH)2 vitamin D (1,25D) is tightly regulated in kidney proximal tubules (PT) by FGF23, PTH, and 1,25D itself, and is markedly disturbed in diseases involving these hormones. FGF23 and 1,25D enhance, whereas PTH suppresses, 1,25D catabolic enzyme CYP24A1, with exactly reciprocal control of anabolic CYP27B1. However, the PT transcription factors (TF) directing FGF23-mediated 1,25D regulation are completely unknown, representing a major unresolved question.
Methods
10X Multiome on kidneys from mouse models of gain/loss of FGF23 function was used to isolate novel, differential pathways at single single-cell level. Validation and dynamic TF activity was tested in vitro. Co-injections of FGF23 (3 h) and PTH (2 h) in WT mice tested intra-regulatory function, with parallel co-treatments of FGF23 and SIK inhibitor (SIKi) in vitro.
Results
10X Multiomics revealed FGF23 injection into WT mice increased the TF Etv1 mRNA specifically in PTS1-2 cells, co-localizing with Cyp24a1; whereas KL-KO mice highly suppressed Etv1 and promoter accessibility (>90%; p<0.05). With FGF23 injection nuclear ETV1 accumulated in megalin-positive PT cells at 1-4 h as determined by IF and nuclei isolates. In vitro, a human ETV1 cDNA increased CYP24A1 (4-6 fold; p<0.01) in HEK-mKL and RPTEC cells, and ETV1 shRNA blocked FGF23 increases in CYP24A1. Native ETV1 protein was dynamically induced by FGF23 (1, 4, 24 h) in HEK-mKL cells, whereas 1,25D had no effect, but instead highly stabilized ETV1-VDR complexes by IP. Sequential injections of FGF23 and PTH to mice showed decreased nuclear ETV1 protein in vivo, and a PTH mimetic SIKi rapidly ablated ETV1 protein in vitro which was reversed by a proteasome inhibitor. Finally, IP of ETV1-FLAG cDNAs identified FGF23 as a direct ETV1 activator by inhibiting an ancient system of COP1-mediated ubiquitination/proteasome degradation, consistent with PT cell COP1 nuclear export in vivo.
Conclusion
In sum, ETV1 is a PT-specific TF activated by FGF23 that directly interacts with VDR and increases Cyp24a1. In contrast, PTH and SIKi reduced ETV1, via the proteasome. Thus, ETV1 is a novel component directing balanced control of systemic 1,25D, opening new connections for strategies critically needed for vitamin D- and FGF23-related disorders.