Suppression of Angiotensin-(1-7) on the Disruption of Blood-Brain Barrier in Rat of Brain Glioma

Pathol Oncol Res. 2019 Jan;25(1):429-435. doi: 10.1007/s12253-018-0471-z. Epub 2018 Sep 18.

Abstract

Glioblastoma multiforme (GBM) is the most primary brain tumor, specially characterized with the damage of blood-brain barrier (BBB). The Ang-(1-7) was proven to have an inhibitory effect on glioblastoma growth. However, its role on blood-brain barrier (BBB) and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved the damage of blood-brain barrier in rats with intracranial U87 gliomas as evaluated by magnetic resonance imaging (MRI). Furthermore, its treatment attenuated BBB permeability, tumor growth and edema formation. Similarly, Ang-(1-7) also decreased U87 glioma cells barrier permeability in vitro. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and ZO-1) expression levels both in rats and U87 glioma cells by affecting the activation of JNK pathway. SP600125, an inhibitor of JNK, significantly enhanced the expression of Claudin-5 and ZO-1, and decreased the disruption of BBB and enhanced the efficiency of Ang-(1-7) in glioma rats. Taken together, this study demonstrated a protective role of Ang-(1-7) in glioma-induced blood-brain barrier damage by regulating tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against glioma.

Keywords: Ang-(1–7); Blood–brain barrier; Claudin-5; Glioma; ZO-1.

MeSH terms

  • Angiotensin I / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology
  • Blood-Brain Barrier / drug effects*
  • Brain Edema / drug therapy*
  • Brain Edema / metabolism
  • Brain Edema / pathology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Membrane Permeability / drug effects*
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tight Junctions
  • Tumor Cells, Cultured

Substances

  • Antihypertensive Agents
  • Peptide Fragments
  • Angiotensin I
  • angiotensin I (1-7)