Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus

PLoS One. 2013 Jun 14;8(6):e65549. doi: 10.1371/journal.pone.0065549. Print 2013.


Growth differentiation factor 15 (GDF15), a direct target gene of p53, is a multifunctional member of the TGF-β/BMP superfamily. GDF15 can be induced and is implicated as a key secretory cytokine in response to multiple cellular stimuli. Accumulating evidence indicates that GDF15 is associated with the development and prognosis of diabetes mellitus, while whether GDF15 can be induced by high glucose is unknown. In the present study, we revealed that high glucose could induce GDF15 expression and secretion in cultured human umbilical vein endothelial cells in a ROS- and p53-dependent manner. Inhibition of high glucose-induced GDF15 expression by siRNA demonstrated that adaptively induced GDF15 played a protective role against high glucose-induced human umbilical vein endothelial cell apoptosis via maintaining the active state of PI3K/Akt/eNOS pathway and attenuating NF-κB/JNK pathway activation. The protective effects of GDF15 were probably achieved by inhibiting ROS overproduction in high glucose-treated human umbilical vein endothelial cells in a negative feedback manner. Our results suggest that high glucose can promote GDF15 expression and secretion in human umbilical vein endothelial cells, which in turn attenuates high glucose-induced endothelial cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Binding Sites
  • Cells, Cultured
  • Glucose / physiology*
  • Growth Differentiation Factor 15 / genetics*
  • Growth Differentiation Factor 15 / metabolism
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Smad Proteins / metabolism
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • NF-kappa B
  • Reactive Oxygen Species
  • Smad Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Phosphatidylinositol 3-Kinases
  • MAP Kinase Kinase 4
  • Glucose

Grants and funding

This work was supported by two grants from the National Natural Science Foundation of China: #81072116 (; #30872583 ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.