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

Jingqi Yan, Ziyan Zhang, Honglian Shi

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)115-128
Number of pages14
JournalCellular and Molecular Life Sciences
Volume69
Issue number1
DOIs
Publication statusPublished - Jan 1 2012
Externally publishedYes

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Keywords

  • Blood-brain barrier
  • Diabetes
  • HIF-1
  • High glucose
  • Permeability
  • VEGF

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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