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Aldosterone stimulates fibronectin synthesis in renal fibroblasts through mineralocorticoid receptor-dependent and independent mechanisms

In addition to its role in regulation of salt transport in the kidney, the mineralocorticoid hormone aldosterone plays an independent role as a mediator of kidney injury and progression of chronic kidney disease. Studies in both animal models and patients have shown that aldosterone enhances the acc...

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Published in:Gene 2013-11, Vol.531 (1), p.23-30
Main Authors: Chen, Dong, Chen, Zhiyong, Park, Chanyoung, Centrella, Michael, McCarthy, Thomas, Chen, Li, Al-Omari, Ahmed, Moeckel, Gilbert W.
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container_title Gene
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creator Chen, Dong
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description In addition to its role in regulation of salt transport in the kidney, the mineralocorticoid hormone aldosterone plays an independent role as a mediator of kidney injury and progression of chronic kidney disease. Studies in both animal models and patients have shown that aldosterone enhances the accumulation of extracellular matrix and progression of fibrosis in the kidney. However, the cellular mechanisms that lead to aldosterone-dependent fibrogenesis are poorly understood. In this study we find that aldosterone stimulates fibronectin synthesis through mineralocorticoid receptor (MCR) dependent activation of the c-Jun NH2-terminal protein kinase (JNK) and subsequent phosphorylation of the AP1 transcription factor c-jun, which forms a nuclear complex with the mineralocorticoid receptor in a kidney fibroblast cell line (NRK 49f). Furthermore, MCR-independent phosphorylation of Src family kinase induces IgF1 receptor phosphorylation, which leads to stimulation of the extracellular signal-regulated kinase (ERK1/2) to enhanced fibronectin synthesis. We further find that the IgF1-R-dependent signaling pathway activates fibronectin expression faster than the MCR-dependent pathway. We propose that the mechanisms described in this study are important to aldosterone-dependent progression of interstitial fibrosis in the kidney. Due to the duality of aldosterone-dependent activation of fibronectin synthesis in kidney fibroblasts, MCR-specific inhibitors may not entirely prevent the progression of fibrosis by aldosterone in the kidney.
doi_str_mv 10.1016/j.gene.2013.08.047
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Studies in both animal models and patients have shown that aldosterone enhances the accumulation of extracellular matrix and progression of fibrosis in the kidney. However, the cellular mechanisms that lead to aldosterone-dependent fibrogenesis are poorly understood. In this study we find that aldosterone stimulates fibronectin synthesis through mineralocorticoid receptor (MCR) dependent activation of the c-Jun NH2-terminal protein kinase (JNK) and subsequent phosphorylation of the AP1 transcription factor c-jun, which forms a nuclear complex with the mineralocorticoid receptor in a kidney fibroblast cell line (NRK 49f). Furthermore, MCR-independent phosphorylation of Src family kinase induces IgF1 receptor phosphorylation, which leads to stimulation of the extracellular signal-regulated kinase (ERK1/2) to enhanced fibronectin synthesis. We further find that the IgF1-R-dependent signaling pathway activates fibronectin expression faster than the MCR-dependent pathway. We propose that the mechanisms described in this study are important to aldosterone-dependent progression of interstitial fibrosis in the kidney. Due to the duality of aldosterone-dependent activation of fibronectin synthesis in kidney fibroblasts, MCR-specific inhibitors may not entirely prevent the progression of fibrosis by aldosterone in the kidney.</description><identifier>ISSN: 0378-1119</identifier><identifier>EISSN: 1879-0038</identifier><identifier>DOI: 10.1016/j.gene.2013.08.047</identifier><identifier>PMID: 23994292</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Aldosterone ; Aldosterone - pharmacology ; animal models ; Animals ; AP1 ; Cell Line ; Cell Nucleus - metabolism ; extracellular matrix ; fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fibronectin ; fibronectins ; Fibronectins - biosynthesis ; Fibronectins - genetics ; fibrosis ; IgF1-R ; JNK ; Kidney - metabolism ; kidney diseases ; kidneys ; Mineralocorticoid receptor ; mineralocorticoid receptors ; mitogen-activated protein kinase ; Models, Biological ; patients ; phosphorylation ; Protein Binding ; Proto-Oncogene Proteins c-jun - metabolism ; Rats ; Receptor, IGF Type 1 - metabolism ; Receptors, Mineralocorticoid - metabolism ; Signal Transduction ; transcription factors ; Transcription, Genetic - drug effects</subject><ispartof>Gene, 2013-11, Vol.531 (1), p.23-30</ispartof><rights>2013 Elsevier B.V.</rights><rights>2013 Elsevier B.V. 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We propose that the mechanisms described in this study are important to aldosterone-dependent progression of interstitial fibrosis in the kidney. Due to the duality of aldosterone-dependent activation of fibronectin synthesis in kidney fibroblasts, MCR-specific inhibitors may not entirely prevent the progression of fibrosis by aldosterone in the kidney.</description><subject>Aldosterone</subject><subject>Aldosterone - pharmacology</subject><subject>animal models</subject><subject>Animals</subject><subject>AP1</subject><subject>Cell Line</subject><subject>Cell Nucleus - metabolism</subject><subject>extracellular matrix</subject><subject>fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fibronectin</subject><subject>fibronectins</subject><subject>Fibronectins - biosynthesis</subject><subject>Fibronectins - genetics</subject><subject>fibrosis</subject><subject>IgF1-R</subject><subject>JNK</subject><subject>Kidney - metabolism</subject><subject>kidney diseases</subject><subject>kidneys</subject><subject>Mineralocorticoid receptor</subject><subject>mineralocorticoid receptors</subject><subject>mitogen-activated protein kinase</subject><subject>Models, Biological</subject><subject>patients</subject><subject>phosphorylation</subject><subject>Protein Binding</subject><subject>Proto-Oncogene Proteins c-jun - metabolism</subject><subject>Rats</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Receptors, Mineralocorticoid - metabolism</subject><subject>Signal Transduction</subject><subject>transcription factors</subject><subject>Transcription, Genetic - drug effects</subject><issn>0378-1119</issn><issn>1879-0038</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9kc1u1DAUhS0EotPCC7CALNlk8F9-LLGpKqBIlVhA15Zj38x4lNiDr1Opj8Bb4ygFdnhjX_u751rnEPKG0T2jrP1w2h8gwJ5TJva031PZPSM71neqplT0z8mOiq6vGWPqglwinmhZTcNfkgsulJJc8R35dT25iBlSDFBh9vMymQxYjX5Yr2z2ocLHkI-AHqtSJAhm2p6HyWDGKh9TXA7HavYBkpmijSl7G70rrIVzjql2cIbgIOTKBFdU_tUz2KMJHmd8RV6MZkJ4_bRfkfvPn37c3NZ33758vbm-q62Uba472g7QDaLjbOxUI8WgjBGtc6bhVhjZygaEagxY1nPKxWiNabkDVg52oEpckfeb7jnFnwtg1rNHC9NkAsQFNZNSiL5VnSgo31CbImKCUZ-Tn0161IzqNQJ90msEeo1A016XCErT2yf9ZZjB_W3543kB3m3AaKI2h-RR338vCk2Jp4yW69yPGwHFhwcPSaP1ECw4XyzN2kX_vx_8Bor6pfs</recordid><startdate>20131115</startdate><enddate>20131115</enddate><creator>Chen, Dong</creator><creator>Chen, Zhiyong</creator><creator>Park, Chanyoung</creator><creator>Centrella, Michael</creator><creator>McCarthy, Thomas</creator><creator>Chen, Li</creator><creator>Al-Omari, Ahmed</creator><creator>Moeckel, Gilbert W.</creator><general>Elsevier B.V</general><scope>FBQ</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>7X8</scope></search><sort><creationdate>20131115</creationdate><title>Aldosterone stimulates fibronectin synthesis in renal fibroblasts through mineralocorticoid receptor-dependent and independent mechanisms</title><author>Chen, Dong ; 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Studies in both animal models and patients have shown that aldosterone enhances the accumulation of extracellular matrix and progression of fibrosis in the kidney. However, the cellular mechanisms that lead to aldosterone-dependent fibrogenesis are poorly understood. In this study we find that aldosterone stimulates fibronectin synthesis through mineralocorticoid receptor (MCR) dependent activation of the c-Jun NH2-terminal protein kinase (JNK) and subsequent phosphorylation of the AP1 transcription factor c-jun, which forms a nuclear complex with the mineralocorticoid receptor in a kidney fibroblast cell line (NRK 49f). Furthermore, MCR-independent phosphorylation of Src family kinase induces IgF1 receptor phosphorylation, which leads to stimulation of the extracellular signal-regulated kinase (ERK1/2) to enhanced fibronectin synthesis. We further find that the IgF1-R-dependent signaling pathway activates fibronectin expression faster than the MCR-dependent pathway. We propose that the mechanisms described in this study are important to aldosterone-dependent progression of interstitial fibrosis in the kidney. Due to the duality of aldosterone-dependent activation of fibronectin synthesis in kidney fibroblasts, MCR-specific inhibitors may not entirely prevent the progression of fibrosis by aldosterone in the kidney.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>23994292</pmid><doi>10.1016/j.gene.2013.08.047</doi><tpages>8</tpages></addata></record>
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ispartof Gene, 2013-11, Vol.531 (1), p.23-30
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subjects Aldosterone
Aldosterone - pharmacology
animal models
Animals
AP1
Cell Line
Cell Nucleus - metabolism
extracellular matrix
fibroblasts
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibronectin
fibronectins
Fibronectins - biosynthesis
Fibronectins - genetics
fibrosis
IgF1-R
JNK
Kidney - metabolism
kidney diseases
kidneys
Mineralocorticoid receptor
mineralocorticoid receptors
mitogen-activated protein kinase
Models, Biological
patients
phosphorylation
Protein Binding
Proto-Oncogene Proteins c-jun - metabolism
Rats
Receptor, IGF Type 1 - metabolism
Receptors, Mineralocorticoid - metabolism
Signal Transduction
transcription factors
Transcription, Genetic - drug effects
title Aldosterone stimulates fibronectin synthesis in renal fibroblasts through mineralocorticoid receptor-dependent and independent mechanisms
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