Vitamin D metabolism in the kidney: Regulation by phosphorus and fibroblast growth factor 23

2011 ◽  
Vol 347 (1-2) ◽  
pp. 17-24 ◽  
Author(s):  
Farzana Perwad ◽  
Anthony A. Portale
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism

scholarly journals Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5269-5279 ◽  
Author(s):  
Xiuying Bai ◽  
Dengshun Miao ◽  
Jiarong Li ◽  
David Goltzman ◽  
Andrew C. Karaplis
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Fibroblast Growth Factor ◽  
Calcium Homeostasis ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D3 ◽  
Circulating Levels

Abstract Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D3) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D3 production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

scholarly journals Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

2018 ◽  
Vol 29 (10) ◽  
pp. 2583-2592 ◽  
Author(s):  
Cassianne Robinson-Cohen ◽  
Traci M. Bartz ◽  
Dongbing Lai ◽  
T. Alp Ikizler ◽  
Munro Peacock ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Genetic Variants ◽  
Fibroblast Growth Factor 23 ◽  
Phosphate Transport ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Genome Wide ◽  
Fgf23 Concentration

BackgroundFibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.MethodsWe performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log–transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.ResultsWe discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10−24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.ConclusionsCommon genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy ofHypMice

2014 ◽  
Vol 29 (7) ◽  
pp. 1627-1638 ◽  
Author(s):  
Yasuhisa Ohata ◽  
Miwa Yamazaki ◽  
Masanobu Kawai ◽  
Naoko Tsugawa ◽  
Kanako Tachikawa ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
In Pregnancy

scholarly journals The Gut Microbiota Regulates Endocrine Vitamin D Metabolism through Fibroblast Growth Factor 23

2018 ◽  
Vol 9 ◽  
Author(s):  
Stephanie A. Bora ◽  
Mary J. Kennett ◽  
Philip B. Smith ◽  
Andrew D. Patterson ◽  
Margherita T. Cantorna
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Gut Microbiota ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism

FP469THE EFFECTS OF FIBROBLAST GROWTH FACTOR 23 AND PTH ON VITAMIN D METABOLISM IN PATIENTS WITH KIDNEY TRANSPLANT

2019 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Corrado Vitale ◽  
Cristina Guiotto ◽  
Giorgio Soragna ◽  
Amelia Rodofili ◽  
Diega Marranca ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kidney Transplant ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism

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

Nephron ◽  
2015 ◽  
Vol 130 (2) ◽  
pp. 119-126 ◽  
Author(s):  
Shinya Nakatani ◽  
Ayumi Nakatani ◽  
Naoko Tsugawa ◽  
Shinsuke Yamada ◽  
Katsuhito Mori ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism

scholarly journals Analysis of the Biochemical Mechanisms for the Endocrine Actions of Fibroblast Growth Factor-23

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4647-4656 ◽  
Author(s):  
Xijie Yu ◽  
Omar A. Ibrahimi ◽  
Regina Goetz ◽  
Fuming Zhang ◽  
Siobhan I. Davis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Proximal Tubule ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Fibroblast Growth Factor 23 ◽  
Proximal Tubule Cell ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Splice Isoforms

Fibroblast growth factor (FGF)-23 has emerged as an endocrine regulator of phosphate and of vitamin D metabolism. It is produced in bone and, unlike other FGFs, circulates in the bloodstream to ultimately regulate phosphate handling and vitamin D production in the kidney. Presently, it is unknown which of the seven principal FGF receptors (FGFRs) transmits FGF23 biological activity. Furthermore, the molecular basis for the endocrine mode of FGF23 action is unclear. Herein, we performed surface plasmon resonance and mitogenesis experiments to comprehensively characterize receptor binding specificity. Our data demonstrate that FGF23 binds and activates the c splice isoforms of FGFR1–3, as well as FGFR4, but not the b splice isoforms of FGFR1–3. Interestingly, highly sulfated and longer glycosaminoglycan (GAG) species were capable of promoting FGF23 mitogenic activity. We also show that FGF23 induces tyrosine phosphorylation and inhibits sodium-phosphate cotransporter Npt2a mRNA expression using opossum kidney cells, a model kidney proximal tubule cell line. Removal of cell surface GAGs abolishes the effects of FGF23, and exogenous highly sulfated GAG is capable of restoring FGF23 activity, suggesting that proximal tubule cells naturally express GAGs that are permissive for FGF23 action. We propose that FGF23 signals through multiple FGFRs and that the unique endocrine actions of FGF23 involve escape from FGF23-producing cells and circulation to the kidney, where highly sulfated GAGs most likely act as cofactors for FGF23 activity. Our biochemical findings provide important insights into the molecular mechanisms by which dysregulated FGF23 signaling leads to disorders of hyper- and hypophosphatemia.

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