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- Title
High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells.
- Authors
Kitsunai, Hiroya; Makino, Yuichi; Sakagami, Hidemitsu; Mizumoto, Katsutoshi; Yanagimachi, Tsuyoshi; Atageldiyeva, Kuralay; Takeda, Yasutaka; Fujita, Yukihiro; Abiko, Atsuko; Takiyama, Yumi; Haneda, Masakazu
- 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-1 α and 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 (Ch REBP) 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 by DNA microarray analysis and identified platelet-derived growth factor-C ( PDGF-C) as a novel target gene of Ch REBP. In streptozotocin-induced diabetic mice, glomerular cells showed a significant increase in PDGF-C expression; the ratio of PDGF-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 of PDGF-C protein by 1.9-fold. Knock-down of Ch REBP abrogated this induction response. Upregulated PDGF-C contributed to the production of type IV and type VI collagen, possibly via an autocrine mechanism. Interestingly, urinary PDGF-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 of PDGF-C via Ch REBP in 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.
- Subjects
GENE expression; GENETIC regulation; HYPOXIA-inducible factor 1; HYPOXIA-inducible factors; EXTRACELLULAR matrix
- Publication
Physiological Reports, 2016, Vol 4, Issue 6, pn/a
- ISSN
2051-817X
- Publication type
Article
- DOI
10.14814/phy2.12730