HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells

Cell Mol Life Sci. 2012 Jan;69(1):115-28. doi: 10.1007/s00018-011-0731-5. Epub 2011 May 27.


Experimental evidence from human patients and animal models of diabetes has demonstrated that hyperglycemia increases blood-brain barrier (BBB) permeability, which is associated with increased risk of neurological dysfunction. However, the mechanism underlying high glucose-induced BBB disruption is not understood. Here we investigated the role of hypoxia-inducible factor-1 (HIF-1) in high glucose-induced endothelial permeability in vitro using mouse brain microvascular endothelial cells (b.End3). Our results demonstrated that high glucose (30 mM) upregulated the protein level of HIF-1α, the regulatable subunit of HIF-1, and increased the transcriptional activity of HIF-1 in the endothelial cells. At the same time, high glucose increased the paracellular permeability associated with diminished expression and disrupted continuity of tight junction proteins occludin and zona occludens protein-1 (ZO-1) of the endothelial cells. Upregulating HIF-1 activity by cobalt chloride increased the paracellular permeability of the endothelial cells exposed to normal glucose (5.5 mM). In contrast, downregulating HIF-1 activity by HIF-1α inhibitors and HIF-1α specific siRNA ameliorated the increased paracellular permeability and the alterations of distribution pattern of occludin and ZO-1 induced by high glucose. In addition, high glucose increased expression of vascular endothelial growth factor (VEGF), a downstream gene of HIF-1. Inhibiting VEGF improved the expression pattern of occludin and ZO-1, and attenuated the endothelial leakage. Furthermore, key results were confirmed in human brain microvascular endothelial cells. These results strongly indicate that HIF-1 plays an important role in high glucose-induced BBB dysfunction. The results will help us understand the molecular mechanisms involved in hyperglycemia-induced BBB dysfunction and neurological outcomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Blood-Brain Barrier* / metabolism
  • Blood-Brain Barrier* / physiopathology
  • Brain / metabolism
  • Endothelial Cells / metabolism
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Glucose / metabolism*
  • Humans
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Indazoles / pharmacology
  • Membrane Proteins / metabolism
  • Mice
  • Occludin
  • Permeability
  • Phosphoproteins / metabolism
  • Tight Junctions / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism*
  • Zonula Occludens-1 Protein


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • Ocln protein, mouse
  • Phosphoproteins
  • TJP1 protein, human
  • Tjp1 protein, mouse
  • Vascular Endothelial Growth Factor A
  • Zonula Occludens-1 Protein
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • Estradiol
  • 2-Methoxyestradiol
  • Glucose