Abstract
Estrogen has been demonstrated to exert beneficial effects on kidney; however, the role of G protein-coupled estrogen receptor 1 (GPER) is still uncertain. In the present study, we investigated the effect of 17β-estradiol and GPER agonist Fulvestrant on extracellular matrix production under transforming growth factor-β1 (TGF-β1) stimulation in human and rat mesangial cells. As a result, 17β-estradiol and Fulvestrant inhibit TGF-β1-induced type IV collagen and fibronectin expression in a dose-dependent manner, by suppressing acute Smad2/3 phosphorylation and Smad4 complex formation. Furthermore, estrogen and Fulvestrant also down-regulate Smad signaling by promoting ubiquitin/proteasome-dependent Smad2 degradation. These effects could be abrogated by receptor antagonist G-15 or GPER gene knockdown. GPER is also required for estrogen and Fulvestrant to regulate mesangial cell migration in response to TGF-β1. To conclude, GPER is crucial in modulating glomerular mesangial cell function including extracellular matrix production and migration.
Keywords:
Cell migration; Estrogen receptor; Extracellular matrix; G protein-coupled estrogen receptor 1; Mesangial cell.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzodioxoles / pharmacology
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Cell Movement
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Collagen Type IV / genetics
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Collagen Type IV / metabolism
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Dose-Response Relationship, Drug
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Estradiol / analogs & derivatives
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Estradiol / pharmacology*
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Extracellular Matrix / drug effects
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Extracellular Matrix / metabolism*
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Female
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Fibronectins / genetics
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Fibronectins / metabolism
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Fulvestrant
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Gene Expression Regulation
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Humans
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Mesangial Cells / cytology
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Mesangial Cells / drug effects
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Mesangial Cells / metabolism*
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Primary Cell Culture
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Quinolines / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / agonists
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / genetics*
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Transforming Growth Factor beta1 / pharmacology*
Substances
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4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline
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Benzodioxoles
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Collagen Type IV
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Fibronectins
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Gper1 protein, rat
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Quinolines
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Smad2 Protein
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Smad2 protein, rat
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Smad3 Protein
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Smad3 protein, rat
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Smad4 Protein
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Smad4 protein, rat
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Transforming Growth Factor beta1
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Fulvestrant
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Estradiol
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Proteasome Endopeptidase Complex