FGF-23 Regulates CYP27B1 Transcription in the Kidney and in Extra-Renal Tissues

Abstract

The mitochondrial enzyme 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by the CYP27B1 gene, converts 25OHD to the biological active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Renal 1α-hydroxylase activity is the principal determinant of the circulating 1,25(OH)2D concentration and enzyme activity is tightly regulated by several factors. Fibroblast growth factor-23 (FGF-23) decreases serum 1,25(OH)2D concentrations by suppressing CYP27B1 mRNA abundance in mice. In extra-renal tissues, 1α-hydroxylase is responsible for local 1,25(OH)2D synthesis, which has important paracrine actions, but whether FGF-23 regulates CYP27B1 gene expression in extra-renal tissues is unknown. We sought to determine whether FGF-23 regulates CYP27B1 transcription in the kidney and whether extra-renal tissues are target sites for FGF-23-induced suppression of CYP27B1. In HEK293 cells transfected with the human CYP27B1 promoter, FGF-23 suppressed promoter activity by 70%, and the suppressive effect was blocked by CI-1040, a specific inhibitor of extracellular signal regulated kinase 1/2. To examine CYP27B1 transcriptional activity in vivo, we crossed fgf-23 null mice with mice bearing the CYP27B1 promoter-driven luciferase transgene (1α-Luc). In the kidney of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity was increased by 3-fold compared to that in wild-type/1α-Luc mice. Intraperitoneal injection of FGF-23 suppressed renal CYP27B1 promoter activity and protein expression by 26% and 60% respectively, and the suppressive effect was blocked by PD0325901, an ERK1/2 inhibitor. These findings provide evidence that FGF-23 suppresses CYP27B1 transcription in the kidney. Furthermore, we demonstrate that in FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA abundance are increased in several extra-renal sites. In the heart of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA were 2- and 5-fold higher, respectively, than in control mice. We also observed a 3- to 10-fold increase in CYP27B1 mRNA abundance in the lung, spleen, aorta and testis of FGF-23 null/1α-Luc mice. Thus, we have identified novel extra-renal target sites for FGF-23-mediated regulation of CYP27B1.

Cloning of a functional 25‐hydroxyvitamin D‐1α‐hydroxylase in zebrafish (Danio rerio)

“…In Figure , the heart exhibited the lowest expression relative to the other organs analysed while the kidney, as expected, had the highest (17 and 65‐fold greater than heart) and the spleen had intermediate levels (four to sevenfold higher compared to heart). These findings are consistent with reports from other animals that revealed low but detectable expression of CYP27B1 in spleen and heart …”

Fibroblast Growth Factor-23—A Potential Uremic Toxin

“…FGF23 inhibits the synthesis of CYP27B1, which is an enzyme involved in the conversion of 25OH-D into the more active 1,25(OH) 2 -D. Moreover, FGF23 upregulates the expression of another enzyme: CYP24A1, which is essential in the catabolism of 1,25(OH) 2 -D, as well as the 25OH-D it stimulates the synthesis of 1,24,25(OH) 3 -D or 24,25(OH) 2 -D [14,15]. …”

“…An additional mechanism involved in the elevation of plasma FGF23 concentration in CKD is the decrease of the renal expression of Klotho concomitant with the deterioration of kidney function. This causes the renal “resistance” to circulating FGF23 [14,15,16]. An interesting recent finding is the fact that both inflammatory status and/or iron deficiency can be other potent contributors to the increased FGF23 concentration in patients with CKD.…”

Fibroblast Growth Factor-23 and Vitamin D Metabolism in Subjects with eGFR ≥60 ml/min/1.73 m²

“…Although both FGF-23 and PTH exhibit potent phosphaturic effects, they exert opposing effects on vitamin D metabolism [6,8,9,10,11,12,13,14,15,16,17,18]. PTH stimulates the conversion of vitamin D from 25-hydroxyvitamin D (25-OH-D) to 1,25-dihydroxyvitamin D (1,25(OH) 2 D) [8,9,12] and inhibits the conversion of 25-OH-D to 24,25-dihydroxyvitamin D (24,25(OH) 2 D) [10,11].…”

“…PTH stimulates the conversion of vitamin D from 25-hydroxyvitamin D (25-OH-D) to 1,25-dihydroxyvitamin D (1,25(OH) 2 D) [8,9,12] and inhibits the conversion of 25-OH-D to 24,25-dihydroxyvitamin D (24,25(OH) 2 D) [10,11]. In contrast, FGF-23 stimulates the production of 24,25(OH) 2 D from 25-OH-D [14,15,17] with an inhibitory effect on 1,25(OH) 2 D production from 25-OH-D [13,16,18]. Therefore, determination of serum levels of these 3 vitamin D metabolites, along with FGF-23 and intact-PTH, could allow us to distinguish the effect of FGF-23 from that of PTH.…”