Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury.
Several lines of clinical and experimental evidence suggest an important role of the renin-angiotensin system in ischemic brain injury although the cellular regulation of the angiotensin AT1 and AT2 receptors and their potential relevance in this condition have not yet been clearly defined. We first assessed the regulation of brain AT1 and AT2 receptors in response to transient unilateral medial cerebral artery occlusion in rats by real-time RT-PCR, Western blot, and immunofluorescence labeling. AT2 receptors in the peri-infarct zone were significantly upregulated 2 days after transient focal cerebral ischemia. Increased AT2 receptors, which were abundantly distributed in a large number of brain regions adjacent to the infarct area including cerebral frontal cortex, piriform cortex, striatum, and hippocampus, were exclusively expressed in neurons. By contrast, AT1 receptors, which remained unaltered, were mainly expressed in astrocytes. In neurons of ischemic striatum, increased AT2 receptors were associated with intense neurite outgrowth. Blockade of central AT2 receptors with PD123177 abolished the neuroprotective effects of central AT1 receptor blockade with irbesartan on infarct size and neurological outcome. In primary cortical neurons, stimulation of AT2 receptors supported neuronal survival and neurite outgrowth. Our data indicate that cerebral AT2 receptors exert neuroprotective actions in response to ischemia-induced neuronal injury, possibly by supporting neuronal survival and neurite outgrowth in peri-ischemic brain areas.
Li
Jun
J
Center for Cardiovascular Research/Institute of Pharmacology and Toxicology, Charité-University Medicine Berlin, Germany.
Culman
Juraj
J
Hörtnagl
Heide
H
Zhao
Yi
Y
Gerova
Nadezhda
N
Timm
Melanie
M
Blume
Annegret
A
Zimmermann
Mathias
M
Seidel
Kerstin
K
Dirnagl
Ulrich
U
Unger
Thomas
T
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001253:Astrocytes / Q000737:chemistry; D015153:Blotting, Western; D001927:Brain Diseases / Q000209:etiology* / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002544:Cerebral Infarction / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D008297:Male; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II