ETV1 Couples Reciprocal FGF23 and PTH Signaling to Renal CYP24A1 Regulation

Active vitamin D [1,25(OH)2D3; 1,25D] synthesis is finely balanced in kidney proximal tubules by the catabolic enzyme CYP24A1 and anabolic CYP27B1. Fibroblast growth factor 23 (FGF23) and 1,25D lower 1,25D by increasing CYP24A1 and suppressing CYP27B1, opposing the actions of parathyroid hormone (PTH). Following FGF23 injections, scRNAseq identified E twenty-six (ETS) member ETV1 as specifically induced in PT S1-S2 cells with Cyp24a1. ETV1 was rapidly recruited to Cyp24a1 enhancers mediating FGF23 and PTH responses, overlapping with VDR, whereas PTH nearly eliminated ETV1 occupancy (4,790 sites to 22). In vitro, ETV1 induced CYP24A1, and ETV1-VDR interactions were greatly enhanced by 1,25D. Deletion of Etv1 from mouse kidney epithelium caused FGF23 resistance with elevated iFGF23, and a PTH mimetic salt-inducible kinase inhibitor enhanced COP1-mediated ETV1 degradation. Together, ETV1 is identified as a mediator of reciprocal FGF23 and PTH control of renal vitamin D metabolism, revealing novel mechanisms governing endocrine mineral homeostasis.