title: High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells.
abstract: Persistent high concentration of glucose causes cellular stress and damage in diabetes via derangement of gene expressions. We previously reported high glucose activates hypoxia-inducible factor-1αand downstream gene expression in mesangial cells, leading to an extracellular matrix expansion in the glomeruli. A glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP) is a key mediator for such perturbation of gene regulation. To provide insight into glucose-mediated gene regulation in mesangial cells, we performed chromatin immunoprecipitation followed byDNAmicroarray analysis and identified platelet-derived growth factor-C (PDGF-C) as a novel target gene of ChREBP In streptozotocin-induced diabetic mice, glomerular cells showed a significant increase inPDGF-C expression; the ratio ofPDGF-C-positive cells to the total number glomerular cells demonstrated more than threefold increase when compared with control animals. In cultured human mesangial cells, high glucose enhanced expression ofPDGF-C protein by 1.9-fold. Knock-down of ChREBPabrogated this induction response. UpregulatedPDGF-C contributed to the production of typeIVand typeVIcollagen, possibly via an autocrine mechanism. Interestingly, urinaryPDGF-C levels in diabetic model mice were significantly elevated in a fashion similar to urinary albumin. Taken together, we hypothesize that a high glucose-mediated induction ofPDGF-C via ChREBPin mesangial cells contributes to the development of glomerular mesangial expansion in diabetes, which may provide a platform for novel predictive and therapeutic strategies for diabetic nephropathy.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kitsunai
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan makino@asahikawa-med.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Mizumoto
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yanagimachi
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kuralay
authors.initials: K
authors.lastname: Atageldiyeva
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Abiko
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takiyama
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications*; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000652:urine; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D024141:Collagen Type IV; D024142:Collagen Type VI; D008222:Lymphokines; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; C411423:platelet-derived growth factor C
keywords: Carbohydrate response element‐binding protein; diabetic nephropathy; mesangial cells; platelet‐derived growth factor‐C; transcription factor