Dataset Information

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism.

ABSTRACT: Fibroblast Growth Factor 23 (FGF23) is a bone-derived hormone that reduces kidney phosphate reabsorption and 1,25(OH)2 vitamin D synthesis via its required co-receptor alpha-Klotho. To identify novel genes that could serve as targets to control FGF23-mediated mineral metabolism, gene array and single-cell RNA sequencing were performed in wild type mouse kidneys. Gene array demonstrated that heparin-binding EGF-like growth factor (HBEGF) was significantly up-regulated following one-hour FGF23 treatment of wild type mice. Mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of Egr1, and increased Cyp24a1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGF-receptor expression mostly in the proximal tubule, and alpha-Klotho expression in proximal and distal tubule segments. In alpha-Klotho-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased Egr1 and Cyp24a1 with correction of basally elevated Cyp27b1. Additionally, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased Cyp27b1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 cells with stable alpha-Klotho expression, FGF23 and HBEGF increased CYP24A1 mRNA expression. HBEGF, but not FGF23 bioactivity was blocked with EGF-receptor inhibition. Thus, our findings support that the paracrine/autocrine factor HBEGF could play novel roles in controlling genes downstream of FGF23 via targeting common signaling pathways.

SUBMITTER: Ni P

PROVIDER: S-EPMC7914218 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism.

Ni Pu P Clinkenbeard Erica L EL Noonan Megan L ML Richardville Joseph M JM McClintick Jeanette J Hato Takashi T Janosevic Danielle D Cheng Ying-Hua YH El-Achkar Tarek M TM Eadon Michael T MT Dagher Pierre C PC White Kenneth E KE

Kidney international 20201104 3

Fibroblast Growth Factor 23 (FGF23) is a bone-derived hormone that reduces kidney phosphate reabsorption and 1,25(OH)2 vitamin D synthesis via its required co-receptor alpha-Klotho. To identify novel genes that could serve as targets to control FGF23-mediated mineral metabolism, gene array and single-cell RNA sequencing were performed in wild type mouse kidneys. Gene array demonstrated that heparin-binding EGF-like growth factor (HBEGF) was significantly up-regulated following one-hour FGF23 tre ...[more]

PMID: 33159963

Similar Datasets

Project description:Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C-terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than ≥50mcg/dl. Longitudinal changes in iron predicted changes in C-terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C-terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women.

Project description:Background and objectivesIncreases in fibroblast growth factor 23 precede kidney function decline in autosomal dominant polycystic kidney disease; however, the role of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease has not been well characterized.Design, setting, participants & measurementsWe measured intact fibroblast growth factor 23 levels in baseline serum samples from 1002 participants in the HALT-PKD Study A (n=540; mean eGFR =91±17 ml/min per 1.73 m2) and B (n=462; mean eGFR =48±12 ml/min per 1.73 m2). We used linear mixed and Cox proportional hazards models to test associations between fibroblast growth factor 23 and eGFR decline, percentage change in height-adjusted total kidney volume, and composite of time to 50% reduction in eGFR, onset of ESRD, or death.ResultsMedian (interquartile range) intact fibroblast growth factor 23 was 44 (33-56) pg/ml in HALT-PKD Study A and 69 (50-93) pg/ml in Study B. In adjusted models, annualized eGFR decline was significantly faster in the upper fibroblast growth factor 23 quartile (Study A: quartile 4, -3.62; 95% confidence interval, -4.12 to -3.12 versus quartile 1, -2.51; 95% confidence interval, -2.71 to -2.30 ml/min per 1.73 m2; P for trend <0.001; Study B: quartile 4, -3.74; 95% confidence interval, -4.14 to -3.34 versus quartile 1, -2.78; 95% confidence interval, -2.92 to -2.63 ml/min per 1.73 m2; P for trend <0.001). In Study A, higher fibroblast growth factor 23 quartiles were associated with greater longitudinal percentage increase in height-adjusted total kidney volume in adjusted models (quartile 4, 6.76; 95% confidence interval, 5.57 to 7.96 versus quartile 1, 6.04; 95% confidence interval, 5.55 to 6.54; P for trend =0.03). In Study B, compared with the lowest quartile, the highest fibroblast growth factor 23 quartile was associated with elevated risk for the composite outcome (hazard ratio, 3.11; 95% confidence interval, 1.84 to 5.25). Addition of fibroblast growth factor 23 to a model of annualized decline in eGFR≥3.0 ml/min per 1.73 m2 did not improve risk prediction.ConclusionsHigher serum fibroblast growth factor 23 concentration was associated with kidney function decline, height-adjusted total kidney volume percentage increase, and death in patients with autosomal dominant polycystic kidney disease. However, fibroblast growth factor 23 did not substantially improve prediction of rapid kidney function decline.

Dataset Information

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism.

Publications

Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets