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

J Cereb Blood Flow Metab. 2005 Sep;25(9):1159-70. doi: 10.1038/sj.jcbfm.9600115.


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-kappaB (NF-kappaB) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain Chemistry / drug effects*
  • Calcium / pharmacology
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Claudin-5
  • Down-Regulation / physiology
  • Endothelial Cells / drug effects*
  • Gene Products, tat / pharmacology*
  • Genes, ras / genetics
  • HIV-1 / metabolism*
  • Membrane Proteins / biosynthesis*
  • Microscopy, Fluorescence
  • NF-kappa B / drug effects
  • NF-kappa B / physiology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • tat Gene Products, Human Immunodeficiency Virus


  • Chelating Agents
  • Claudin-5
  • Cldn5 protein, rat
  • Gene Products, tat
  • Membrane Proteins
  • NF-kappa B
  • RNA, Messenger
  • tat Gene Products, Human Immunodeficiency Virus
  • Vascular Endothelial Growth Factor Receptor-2
  • Calcium