title: Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1 protein-smooth muscle α-actin (SMA) signal transduction in diabetic nephropathy.
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.
authors.affiliation: Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan. abeabe@clin.med.tokushima-u.ac.jp
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe
authors.forename: Seiji
authors.initials: S
authors.lastname: Kishi
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: Taichi
authors.initials: T
authors.lastname: Murakami
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D017127:Glycation End Products, Advanced; D051798:Inhibitor of Differentiation Protein 1; D051898:Smad1 Protein; D058127:Transcription Factor 3; D053773:Transforming Growth Factor beta1; C525810:Bmp4 protein, mouse; C497455:Idb1 protein, mouse; C503815:Scx protein, mouse; C497401:Smad1 protein, mouse