title: SOX9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy.
abstract: Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY-related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1α (HIF-1α), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF-1α, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1α and BMP4 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1α and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Health-Bioscience Institute, University of Tokushima, Tokushima 770-8503, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kishi
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.forename: Taichi
authors.initials: T
authors.lastname: Murakami
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: Fumi
authors.initials: F
authors.lastname: Kishi
authors.forename: Motokazu
authors.initials: M
authors.lastname: Matsuura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iehara
authors.forename: Otoya
authors.initials: O
authors.lastname: Ueda
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukushima
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D054338:Cell Transdifferentiation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D024043:Collagen Type II; D017127:Glycation End Products, Advanced; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D055758:SOX9 Transcription Factor; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C527933:Sox9 protein, mouse