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 |
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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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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.</description><identifier>ISSN: 0085-2538</identifier><identifier>EISSN: 1523-1755</identifier><identifier>DOI: 10.1038/ki.2013.332</identifier><identifier>PMID: 24088960</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>Kidney international, 2014-05, Vol.85 (5), p.1103-1111</ispartof><rights>2014 International Society of Nephrology</rights><rights>Copyright Nature Publishing Group May 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-ecb0414eb30a59eac75448fd09a179717ee09a0117ab7b7f69f8b86f58f728783</citedby><cites>FETCH-LOGICAL-c499t-ecb0414eb30a59eac75448fd09a179717ee09a0117ab7b7f69f8b86f58f728783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1520135195?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,64361,64363,64365,72215</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24088960$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jimbo, Rika</creatorcontrib><creatorcontrib>Kawakami-Mori, Fumiko</creatorcontrib><creatorcontrib>Mu, Shengyu</creatorcontrib><creatorcontrib>Hirohama, Daigoro</creatorcontrib><creatorcontrib>Majtan, Bohumil</creatorcontrib><creatorcontrib>Shimizu, Yuichiro</creatorcontrib><creatorcontrib>Yatomi, Yutaka</creatorcontrib><creatorcontrib>Fukumoto, Seiji</creatorcontrib><creatorcontrib>Fujita, Toshiro</creatorcontrib><creatorcontrib>Shimosawa, Tatsuo</creatorcontrib><title>Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency</title><title>Kidney international</title><addtitle>Kidney Int</addtitle><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.</description><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Aortic Diseases - chemically induced</subject><subject>Aortic Diseases - metabolism</subject><subject>Aortic Diseases - pathology</subject><subject>Cell Differentiation - drug effects</subject><subject>Cells, Cultured</subject><subject>chronic kidney disease</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activation</subject><subject>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>fibroblast growth factor 23</subject><subject>Fibroblast Growth Factors - metabolism</subject><subject>Fibroblast Growth Factors - toxicity</subject><subject>Glucuronidase - deficiency</subject><subject>Glucuronidase - genetics</subject><subject>Glucuronidase - metabolism</subject><subject>Klotho</subject><subject>Male</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>Osteoblasts - drug effects</subject><subject>Osteoblasts - metabolism</subject><subject>Osteoblasts - pathology</subject><subject>phosphate</subject><subject>Phosphates - toxicity</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Fibroblast Growth Factor, Type 1 - genetics</subject><subject>Receptor, Fibroblast Growth Factor, Type 1 - metabolism</subject><subject>Recombinant Proteins - toxicity</subject><subject>Renal Insufficiency, Chronic - complications</subject><subject>Renal Insufficiency, Chronic - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Transfection</subject><subject>vascular calcification</subject><subject>Vascular Calcification - chemically induced</subject><subject>Vascular Calcification - metabolism</subject><subject>Vascular Calcification - pathology</subject><issn>0085-2538</issn><issn>1523-1755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqN0c9rFTEQB_Agin1WT94l4EWQfebHZpMcpdgqFnqp55BkJ27afZtnkq30v2-er3oQD54yGT4MzHwRek3JlhKuPtzGLSOUbzlnT9CGCsY7KoV4ijaEKNExwdUJelHKDWl_zclzdMJ6opQeyAbV8-hycrMtFX_P6WedcLC-powZx9Z7mCHbCgXvp1T2Uyu7uIyrhxHf2eLX2Wbs7exjiN7WmBYcF1wnwNYVWDzgFPDXOdUp4RGaia15_xI9C3Yu8OrxPUXfzj9dn33uLq8uvpx9vOx8r3XtwDvS0x4cJ1ZosF6KvldhJNpSqSWVAK0klErrpJNh0EE5NQShgmRKKn6K3h3n7nP6sUKpZhdLW2m2C6S1GCp4r4TkA_kPyihng2ZDo2__ojdpzUtb5KBaEoJq0dT7o_I5lZIhmH2OO5vvDSXmkJu5jeagTcut6TePM1e3g_GP_R1UA-IIoN3rLkI25dctYYwZfDVjiv8c_AAyp6TC</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Jimbo, Rika</creator><creator>Kawakami-Mori, Fumiko</creator><creator>Mu, Shengyu</creator><creator>Hirohama, Daigoro</creator><creator>Majtan, Bohumil</creator><creator>Shimizu, Yuichiro</creator><creator>Yatomi, Yutaka</creator><creator>Fukumoto, Seiji</creator><creator>Fujita, Toshiro</creator><creator>Shimosawa, Tatsuo</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20140501</creationdate><title>Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency</title><author>Jimbo, Rika ; Kawakami-Mori, Fumiko ; Mu, Shengyu ; Hirohama, Daigoro ; Majtan, Bohumil ; Shimizu, Yuichiro ; Yatomi, Yutaka ; Fukumoto, Seiji ; Fujita, Toshiro ; Shimosawa, Tatsuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-ecb0414eb30a59eac75448fd09a179717ee09a0117ab7b7f69f8b86f58f728783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - metabolism</topic><topic>Aorta - pathology</topic><topic>Aortic Diseases - chemically induced</topic><topic>Aortic Diseases - metabolism</topic><topic>Aortic Diseases - pathology</topic><topic>Cell Differentiation - drug effects</topic><topic>Cells, Cultured</topic><topic>chronic kidney disease</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Activation</topic><topic>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>fibroblast growth factor 23</topic><topic>Fibroblast Growth Factors - metabolism</topic><topic>Fibroblast Growth Factors - toxicity</topic><topic>Glucuronidase - deficiency</topic><topic>Glucuronidase - genetics</topic><topic>Glucuronidase - metabolism</topic><topic>Klotho</topic><topic>Male</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>Osteoblasts - drug effects</topic><topic>Osteoblasts - metabolism</topic><topic>Osteoblasts - pathology</topic><topic>phosphate</topic><topic>Phosphates - toxicity</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Fibroblast Growth Factor, Type 1 - genetics</topic><topic>Receptor, Fibroblast Growth Factor, Type 1 - metabolism</topic><topic>Recombinant Proteins - toxicity</topic><topic>Renal Insufficiency, Chronic - complications</topic><topic>Renal Insufficiency, Chronic - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Transfection</topic><topic>vascular calcification</topic><topic>Vascular Calcification - chemically induced</topic><topic>Vascular Calcification - metabolism</topic><topic>Vascular Calcification - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jimbo, Rika</creatorcontrib><creatorcontrib>Kawakami-Mori, Fumiko</creatorcontrib><creatorcontrib>Mu, Shengyu</creatorcontrib><creatorcontrib>Hirohama, Daigoro</creatorcontrib><creatorcontrib>Majtan, Bohumil</creatorcontrib><creatorcontrib>Shimizu, Yuichiro</creatorcontrib><creatorcontrib>Yatomi, Yutaka</creatorcontrib><creatorcontrib>Fukumoto, Seiji</creatorcontrib><creatorcontrib>Fujita, Toshiro</creatorcontrib><creatorcontrib>Shimosawa, Tatsuo</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Kidney international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jimbo, Rika</au><au>Kawakami-Mori, Fumiko</au><au>Mu, Shengyu</au><au>Hirohama, Daigoro</au><au>Majtan, Bohumil</au><au>Shimizu, Yuichiro</au><au>Yatomi, Yutaka</au><au>Fukumoto, Seiji</au><au>Fujita, Toshiro</au><au>Shimosawa, Tatsuo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency</atitle><jtitle>Kidney international</jtitle><addtitle>Kidney Int</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>85</volume><issue>5</issue><spage>1103</spage><epage>1111</epage><pages>1103-1111</pages><issn>0085-2538</issn><eissn>1523-1755</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24088960</pmid><doi>10.1038/ki.2013.332</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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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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