HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells

Kentaro Hayashi, Hong Pu, Jing Tian, Ibolya E. Andras, Yong Woo Lee, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Among the different factors which can contribute to CNS alterations associated with HIV infection, Tat protein is considered to play a critical role. Evidence indicates that Tat can contribute to brain vascular pathology through induction of endothelial cell activation. In the present study, we hypothesized that Tat can affect expression of P-glycoprotein (P-gp) in brain microvascular endothelial cells (BMEC). P-gp is an ATP-dependent cellular efflux transporter which is involved in the removal of specific non-polar molecules, including drugs used for highly active antiretroviral therapy (HAART). Treatment of BMEC with Tat1-72 resulted in P-gp overexpression both at mRNA and protein levels. These alterations were confirmed in vivo in brain vessels of mice injected with Tat1-72 into the hippocampus. Furthermore, pre-treatment of BMEC with SN50, a specific NF-κB inhibitor, protected against Tat1-72-stimulated expression of mdr1a gene, i.e. the gene which encodes for P-gp in rodents. Tat1-72-mediated changes in P-gp expression were correlated with increased rhodamine 123 efflux, indicating the up-regulation of transporter functions of P-gp. These results suggest that Tat-induced overexpression of P-gp in brain microvessels may have significant implications for the development of resistance to HAART and may be a contributing factor for low efficacy of HAART in the CNS.

Original languageEnglish (US)
Pages (from-to)1231-1241
Number of pages11
JournalJournal of neurochemistry
Volume93
Issue number5
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

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Keywords

  • Blood-brain barrier
  • Endothelial cell
  • Highly active antiretroviral therapy
  • HIV-Tat protein
  • Nuclear factor kappa B
  • P-glycoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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