title: 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.
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Portale
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Martin Y H
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Nephrology/Hypertension, Northwestern University-Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Valentin
authors.initials: V
authors.lastname: David
authors.affiliation: Department of Medicine, Division of Nephrology/Hypertension, Northwestern University-Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Aline
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Orthopaedic Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Orthopaedic Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Weikuan
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Farzana
authors.initials: F
authors.lastname: Perwad
mesh_terms: D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000378:metabolism*; D005786:Gene Expression Regulation; D017674:Hypophosphatemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010710:Phosphates / Q000378:metabolism*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000096:biosynthesis; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000096:biosynthesis; D014807:Vitamin D / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C493555:Slc34a1 protein, mouse; C493563:Slc34a3 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23