Characterization of FGF23-Dependent Egr-1 Cistrome in the Mouse Renal Proximal Tubule

Abstract

Fibroblast growth factor 23 (FGF23) is a potent regulator of phosphate (Pi) and vitamin D homeostasis. The transcription factor, early growth response 1 (egr-1), is a biomarker for FGF23-induced activation of the ERK1/2 signaling pathway. We have shown that ERK1/2 signaling blockade suppresses renal egr-1 gene expression and prevents FGF23-induced hypophosphatemia and 1,25-dihydroxyvitamin D (1,25(OH)2D) suppression in mice. To test whether egr-1 itself mediates these renal actions of FGF23, we administered FGF23 to egr-1 -/- and wild-type (WT) mice. In WT mice, FGF23 induced hypophosphatemia and suppressed expression of the renal Na/Pi cotransporters, Npt2a and Npt2c. In FGF23-treated egr-1 -/- mice, hypophosphatemic response was greatly blunted and Na/Pi cotransporter expression was not suppressed. In contrast, FGF23 induced equivalent suppression of serum 1,25(OH)2D concentrations by suppressing renal cyp27b1 and stimulating cyp24a1 mRNA expression in both groups of mice. Thus, downstream of receptor binding and ERK1/2 signaling, we can distinguish the effector pathway that mediates FGF23-dependent inhibition of Pi transport from the pathway that mediates inhibition of 1,25(OH)2D synthesis in the kidney. Furthermore, we demonstrate that the hypophosphatemic effect of FGF23 is significantly blunted in Hyp/egr-1 -/- mice; specifically, serum Pi concentrations and renal Npt2a and Npt2c mRNA expression are significantly higher in Hyp/egr-1 -/- mice than in Hyp mice. We then characterized the egr-1 cistrome in the kidney using ChIP-sequencing and demonstrate recruitment of egr-1 to regulatory DNA elements in proximity to several genes involved in Pi transport. Thus, our data demonstrate that the effect of FGF23 on Pi homeostasis is mediated, at least in part, by activation of egr-1.

Role of ERα in Mediating Female Uterine Transcriptional Responses to IGF1

“…Homeobox motifs are enriched in general in the non-ERE containing ER α binding sites in the mouse uterus ( 16 ). Although a mouse uterine EGR1 cistrome has not been reported, data from mouse kidney indicated that EGR1 tended to interact with sites proximal to TSS ( 20 ), unlike ER α , which exhibits mostly distal interactions ( 16 ). Additionally, epidermal growth factor (EGF) activation of mitogen-activated protein kinase signaling caused EGR1 binding to EGF target genes in prostate cells ( 21 ).…”

FGF23-Klotho signaling axis in the kidney

“…The transcription factor egr-1 is a downstream target of FGF23-induced ERK1/2 activation [14]. However, a recent study using egr-1 null (egr-1 −/− ) and Hyp/egr-1 −/− mice suggested that egr-1 signaling is important for Fgf23-mediated changes in renal phosphate homeostasis, but not for 1,25(OH) 2 D metabolism [58]. As mentioned above, Jak3 −/− mice are characterized by increased serum 1,25(OH) 2 D levels as well as increased 1α-hydroxylase expression in the kidney [32].…”

Fibroblast growth factor-23 may serve as a novel biomarker for renal osteodystrophy progression

“…Fibroblast growth factor (FGF)-23, originally identified in human osteoblasts, is an important hormonal regulator of circulating phosphate and calcitriol via suppressing the Na/Pi IIc cotransporters in proximal tubule cells (7). In the concurrent presence of FGF receptor (FGFR)-1 and the transmembrane protein Klotho, FGF-23 also antagonizes 1α-hydroxylase and Fibroblast growth factor-23 may serve as a novel biomarker for renal osteodystrophy progression subsequently leads to 1,25-dihydroxy vitamin D deficiency and calcium malabsorption, which may initiate the development of bone and mineral disorders (8).…”