High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells

Hiroya Kitsunai, Yuichi Makino, Hidemitsu Sakagami, Katsutoshi Mizumoto, Tsuyoshi Yanagimachi, Kuralay Atageldiyeva, Yasutaka Takeda, Yukihiro Fujita, Atsuko Abiko, Yumi Takiyama, Masakazu Haneda

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

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-1α 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 (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 by DNA microarray 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 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 ChREBP 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 ChREBP 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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalPhysiological Reports
Volume4
Issue number6
DOIs
Publication statusPublished - Mar 1 2016
Externally publishedYes

Keywords

  • Carbohydrate response element-binding protein
  • Diabetic nephropathy
  • Mesangial cells
  • Platelet-derived growth factor-C
  • Transcription factor

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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