angiotensin-i and Brain-Edema

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.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood-Brain Barrier; Brain Edema; Brain Neoplasms; Cell Membrane Permeability; Glioma; Humans; Male; MAP Kinase Signaling System; Peptide Fragments; Rats; Rats, Sprague-Dawley; Tight Junctions; Tumor Cells, Cultured

The angiotensin (Ang) converting enzyme 2 (ACE2)/Ang-(1-7)/Mas receptor pathway is an important component of the renin-angiotensin system and has been suggested to exert beneficial effects in ischemic stroke.. This study explored whether the ACE2/Ang-(1-7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age.. We used three-month and eight-month transgenic mice with neural over-expression of ACE2 (SA) and their age-matched nontransgenic (NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation (OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1-7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species (ROS) production and cell death were measured.. (1) Middle cerebral artery occlusion -induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight-month animals; (2) OGD-induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight-month mice; (3) Ang-(1-7) and A779 had opposite effects on OGD-induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production.. Angiotensin converting enzyme 2/Ang-(1-7)/Mas axis protects brain from ischemic injury via the Nox/ROS signaling pathway, with a greater effect in older animals.

Topics: Age Factors; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Brain; Brain Edema; Brain Ischemia; Cell Death; Female; Glucose; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Male; Membrane Glycoproteins; Mice, Transgenic; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Neurons; Peptide Fragments; Peptidyl-Dipeptidase A; Reactive Oxygen Species; Stroke; Tissue Culture Techniques

We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in the cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase (Nox) isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Brain; Brain Edema; Brain Ischemia; CA1 Region, Hippocampal; Cell Death; Cerebral Cortex; Glucose; Hypoxia; Membrane Glycoproteins; Mice, Transgenic; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Neurons; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Signal Transduction; Stroke; Tissue Culture Techniques

The brain oedema, distribution space (DS) and brain uptake index (BUI), of L-glucose, inulin, B12 vitamin and of three polypeptidic hormones of increasing molecular weight (angiotensin-I, gastrin and insulin) were measured in the rat after sham operation, porto-caval shunt (PCS) or liver ischaemia. At an early stage following PCS or liver ischaemia brain oedema was not constant, and was only demonstrable after liver ischaemia in a large number of animals. Substances without an active transport and with a low diffusion coefficient such as L-glucose and inulin had a very low BUI, unchanged even if the 3H2O brain content or the DS were modified. B12 vitamin, DS and BUI were very high and did not change after liver ischaemia or PCS. Insulin DS and BUI were low in the three groups of animals, whereas it decreased after PCS for gastrin. A significant increase of BUI and DS (without any cerebral oedema) was demonstrated for angiotensin-I, a polypeptidic hormone of molecular weight 1300. This polypeptidic marker is in the same range of MW as the preliminary recently recognized medium-sized molecules which may be involved in the pathogenesis of encephalopathy during experimental acute liver failure. However, not only the MW, but the nature of such polypeptides may be of importance in the genesis of this limited impairment of BBB permeability.

Topics: Acute Disease; Angiotensin I; Animals; Blood-Brain Barrier; Brain Edema; Ischemia; Liver; Male; Molecular Weight; Permeability; Portacaval Shunt, Surgical; Rats; Rats, Inbred Strains; Vitamin B 12