Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells

Ibolya Edit Andras, Hong Pu, Jing Tian, Mária A. Deli, Avindra Nath, Bernhard Hennig, Michal J Toborek

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Exposure of brain microvascular endothelial cells (BMEC) to human immunodeficiency virus-1 (HIV-1) Tat protein can decrease expression and change distribution of tight junction proteins, including claudin-5. Owing to the importance of claudin-5 in maintaining the blood-brain barrier (BBB) integrity, the present study focused on the regulatory mechanisms of Tat-induced alterations of claudin-5 mRNA and protein levels. Real-time reverse- transcription-polymerase chain reaction revealed that claudin-5 mRNA was markedly diminished in BMEC exposed to Tat. However, U0126 (an inhibitor of mitogen-activated protein kinase kinase1/2, MEK1/2) protected against this effect. In addition, inhibition of the vascular endothelial growth factor receptor type 2 (VEGFR-2) by SU1498, phosphatidylinositol-3 kinase (PI-3 K) by LY294002, nuclear factor-κ (NF-κ) by peptide SN50, and intracellular calcium by BAPTA/AM partially prevented Tat-mediated alterations in claudin-5 protein levels and immunoreactivity patterns. In contrast, inhibition of protein kinase C did not affect claudin-5 expression in Tat-treated cells. The present findings indicate that activation of VEGFR-2 and multiple redox-regulated signal transduction pathways are involved in Tat-induced alterations of claudin-5 expression. Because claudins constitute the major backbone of tight junctions, the present data are relevant to the disturbances of the BBB in the course of HIV-1 infection.

Original languageEnglish
Pages (from-to)1159-1170
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number9
DOIs
StatePublished - Dec 8 2005
Externally publishedYes

    Fingerprint

Keywords

  • Blood-brain barrier
  • Brain endothelial cells
  • HIV-1 dementia
  • Signal transduction
  • Tight junctions

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this