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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: András, Ibolya E; Pu, Hong; Tian, Jing; Deli, Mária A; Nath, Avindra; Hennig, Bernhard; Toborek, Michal

Published In J Cereb Blood Flow Metab, (2005 Sep)

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-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.

PubMed ID: 15815581 Exiting the NIEHS site

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

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