Abstract
Activation of mesangial cells (MCs), which is characterized by induction of smooth muscle α-actin (SMA) expression, contributes to a key event in various renal diseases; however, the mechanisms controlling MC differentiation are still largely undefined. Activated Smad1 induced SMA in a dose-dependent manner in MCs. As a direct regulating molecule for SMA, we identified and characterized scleraxis (Scx) as a new phenotype modulator in advanced glycation end product (AGE)-exposed MCs. Scx physically associated with E12 and bound the E-box in the promoter of SMA and negatively regulated the AGE-induced SMA expression. Scx induced expression and secretion of bone morphogenetic protein 4 (BMP4), thereby controlling the Smad1 activation in AGE-treated MCs. In diabetic mice, Scx was concomitantly expressed with SMA in the glomeruli. Inhibitor of differentiation 1 (Id1) was further induced by extended treatment with AGE, thereby dislodging Scx from the SMA promoter. These data suggest that Scx and Id1 are involved in the BMP4-Smad1-SMA signal transduction pathway besides the TGFβ1-Smad1-SMA signaling pathway and modulate phenotypic changes in MCs in diabetic nephropathy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Bone Morphogenetic Protein 4 / biosynthesis*
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Bone Morphogenetic Protein 4 / genetics
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Diabetic Nephropathies / genetics
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Diabetic Nephropathies / metabolism*
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Diabetic Nephropathies / pathology
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Gene Expression Regulation / genetics
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Glomerular Mesangium / metabolism*
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Glomerular Mesangium / pathology
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Glycation End Products, Advanced / genetics
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Glycation End Products, Advanced / metabolism
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Inhibitor of Differentiation Protein 1 / genetics
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Inhibitor of Differentiation Protein 1 / metabolism
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Male
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Mice
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Response Elements / genetics
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Signal Transduction*
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Smad1 Protein / genetics
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Smad1 Protein / metabolism*
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Transcription Factor 3 / genetics
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Transcription Factor 3 / metabolism
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
Substances
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Actins
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Basic Helix-Loop-Helix Transcription Factors
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 4
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Glycation End Products, Advanced
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Idb1 protein, mouse
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Inhibitor of Differentiation Protein 1
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Scx protein, mouse
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Smad1 Protein
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Smad1 protein, mouse
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Transcription Factor 3
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Transforming Growth Factor beta1