Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that acts primarily on the kidney and parathyroid. With declining kidney function there is an increase in circulating FGF23 levels, which is associated with vascular calcification and mortality in chronic kidney disease. Whether F...

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Veröffentlicht in:Kidney international 2014-05, Vol.85 (5), p.1103-1111
Hauptverfasser: Jimbo, Rika, Kawakami-Mori, Fumiko, Mu, Shengyu, Hirohama, Daigoro, Majtan, Bohumil, Shimizu, Yuichiro, Yatomi, Yutaka, Fukumoto, Seiji, Fujita, Toshiro, Shimosawa, Tatsuo
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container_end_page 1111
container_issue 5
container_start_page 1103
container_title Kidney international
container_volume 85
creator Jimbo, Rika
Kawakami-Mori, Fumiko
Mu, Shengyu
Hirohama, Daigoro
Majtan, Bohumil
Shimizu, Yuichiro
Yatomi, Yutaka
Fukumoto, Seiji
Fujita, Toshiro
Shimosawa, Tatsuo
description Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that acts primarily on the kidney and parathyroid. With declining kidney function there is an increase in circulating FGF23 levels, which is associated with vascular calcification and mortality in chronic kidney disease. Whether FGF23 exerts direct effects on vasculature is unclear. We evaluated the expression of Klotho and FGF receptors in rat aortic rings and rat aorta vascular smooth muscle cells maintained in culture by reverse transcription–PCR, western blotting, and immunostaining. Signaling pathways underlying FGF23 effects were assessed by western blotting, and effects of FGF23 on osteogenic markers and phosphate transporters were assessed by real-time reverse transcription–PCR. We detected Klotho and FGFR1 in total aorta but not in vascular smooth muscle cells. FGF23 augmented phosphate-induced vascular calcification in the aortic rings from uremic rats and dose dependently increased ERK1/2 phosphorylation in Klotho-overexpressing but not naive vascular smooth muscle cells. FGF23-induced ERK1/2 phosphorylation was inhibited by SU5402 (FGFR1 inhibitor) and U0126 (MEK inhibitor). FGF23 enhanced phosphate-induced calcification in Klotho-overexpressing vascular smooth muscle cells and increased osteoblastic marker expression, which was inhibited by U0126. In contrast, phosphate transporter expression was not affected by phosphate or FGF23. Thus, FGF23 enhances phosphate-induced vascular calcification by promoting osteoblastic differentiation involving the ERK1/2 pathway.
doi_str_mv 10.1038/ki.2013.332
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FGF23-induced ERK1/2 phosphorylation was inhibited by SU5402 (FGFR1 inhibitor) and U0126 (MEK inhibitor). FGF23 enhanced phosphate-induced calcification in Klotho-overexpressing vascular smooth muscle cells and increased osteoblastic marker expression, which was inhibited by U0126. In contrast, phosphate transporter expression was not affected by phosphate or FGF23. 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FGF23-induced ERK1/2 phosphorylation was inhibited by SU5402 (FGFR1 inhibitor) and U0126 (MEK inhibitor). FGF23 enhanced phosphate-induced calcification in Klotho-overexpressing vascular smooth muscle cells and increased osteoblastic marker expression, which was inhibited by U0126. In contrast, phosphate transporter expression was not affected by phosphate or FGF23. 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subjects Animals
Aorta - drug effects
Aorta - metabolism
Aorta - pathology
Aortic Diseases - chemically induced
Aortic Diseases - metabolism
Aortic Diseases - pathology
Cell Differentiation - drug effects
Cells, Cultured
chronic kidney disease
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases - metabolism
fibroblast growth factor 23
Fibroblast Growth Factors - metabolism
Fibroblast Growth Factors - toxicity
Glucuronidase - deficiency
Glucuronidase - genetics
Glucuronidase - metabolism
Klotho
Male
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Myocytes, Smooth Muscle - pathology
Osteoblasts - drug effects
Osteoblasts - metabolism
Osteoblasts - pathology
phosphate
Phosphates - toxicity
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Receptor, Fibroblast Growth Factor, Type 1 - metabolism
Recombinant Proteins - toxicity
Renal Insufficiency, Chronic - complications
Renal Insufficiency, Chronic - metabolism
Signal Transduction - drug effects
Transfection
vascular calcification
Vascular Calcification - chemically induced
Vascular Calcification - metabolism
Vascular Calcification - pathology
title Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency
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