FGF23 and PTH Directly Control Kidney 1,25(OH)2 Vitamin D3 Metabolism Through the ETS Transcription Factor ETV1 Via Coupled but Reciprocal Mechanisms

ETV1-VDR co-precipitation was greatly enhanced by 1,25D and FGF23+1,25D co-treatment synergistically increased CYP24A1 expression in vitro, and in vivo. Conditional targeting of kidney epithelial Etv1 in mice resulted in ‘FGF23 resistance’ with elevated FGF23 and 1,25D, due to a blockade of Cyp24a1 and altered 1,25D metabolism. FGF23 was shown to inhibit E-3 Ubiquitin ligase Rfwd2 (COP1) nuclear localization, enhancing ETV1 protein stability.

In vivo, PTH injections suppressed nuclear ETV1 protein and opposed FGF23 increases by removing ETV1 from the genome (4,790 sites to 22 sites). In vitro, a ‘PTH mimetic’ SIK inhibitor (SIKi) abolished ETV1 production by enhancing COP1-mediated degradation, whereas COP1 shRNA rescued SIKi-mediated ETV1 suppression. In sum, our findings demonstrate that ETV1 acts as a novel ‘unifying’ TF positively regulating FGF23/KL bioactivity with VDR on Cyp24a1 and suppressive PTH actions, thus opening novel pathways critically needed to address severe diseases involving FGF23 and vitamin D.