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

Physiol Rep. 2016 Mar;4(6):e12730. doi: 10.14814/phy2.12730. Epub 2016 Mar 31.

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.

Keywords: Carbohydrate response element‐binding protein; diabetic nephropathy; mesangial cells; platelet‐derived growth factor‐C; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Binding Sites
  • Blood Glucose / metabolism*
  • Cell Line
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • Collagen Type VI / genetics
  • Collagen Type VI / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / urine
  • Humans
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Lymphokines / urine
  • Male
  • Mesangial Cells / metabolism*
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • Platelet-Derived Growth Factor / urine
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Blood Glucose
  • Collagen Type IV
  • Collagen Type VI
  • Lymphokines
  • MLXIPL protein, human
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Platelet-Derived Growth Factor
  • Transcription Factors
  • platelet-derived growth factor C