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

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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.

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Abbreviations

BBB:

Blood–brain barrier

HIF-1:

Hypoxia-inducible factor 1

VEGF:

Vascular endothelial growth factor

2ME2:

2-Methoxyestradiol

YC-1:

3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl indazole

ZO-1:

Zona occludens protein-1

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Acknowledgments

We thank Dr. Giovanni Melillo (National Cancer Institute-Frederick, Frederick, MD) for kindly providing us with the PGL2TkHRE plasmid and Dr. Rick Dobrowsky for his valuable suggestions and comments. We are indebted to Drs. Eli Michaelis and Mary Lou Michaelis for reading this manuscript and providing very useful suggestions. This research was supported in part by a KUCR startup fund and a KU NFGR award.

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  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 5044, Lawrence, KS, 66045, USA

    Jingqi Yan, Ziyan Zhang & Honglian Shi

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  1. Jingqi Yan
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Yan, J., Zhang, Z. & Shi, H. HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell. Mol. Life Sci. 69, 115–128 (2012). https://doi.org/10.1007/s00018-011-0731-5

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