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Expression of angiotensin receptors in the rat brain after focal cerebral ischemia
Gerova, Nadezhda

HaupttitelExpression of angiotensin receptors in the rat brain after focal cerebral ischemia
TitelvarianteExpression von Angiotensin-Rezeptoren im Rattengehirn nach fokaler zerebraler Ischämie
AutorGerova, Nadezhda
Geburtsort: Sofia
GutachterN.N.
weitere GutachterN.N.
Freie SchlagwörterRAS; angiotensin; AT1; AT2; neuroregeneration; apoptosis; inflammation; cerebral ischemia
DDC610 Medizin und Gesundheit
ZusammenfassungThe Renin-Angiotensin System (RAS) is well known for its function as a regulator of blood pressure and fluid and electrolyte balance with its major effective peptide Angiotensin II. Beside the systemic RAS, a lot of other tissues such as the heart, lungs, liver and the blood vessels have been shown to produce Ang II. The RAS was first known to act only in the periphery. Later RAS and its components were found in the brain and appeared to be autonomous. The development of selective receptor antagonists led to the discovery of the angiotensin receptors. Among these, the AT1 and AT2 receptor subtypes seem to play an important role in ischemic processes. The numerous studies of angiotensin receptors in the last two decades showed that the AT1 receptor was found to be abundant in the mature brain while the AT2 receptor was highly expressed before and during the neonatal period and its expression decreased speedily afterwards. Therefore the AT1 receptor has been studied profusely while much less was known about the AT2 receptor. The majority of the studies were done in vitro. So our aim was to show the distribution of the two receptors in vivo as well as to identify the cells of expression and possible correlations with the apoptosis and inflammation following cerebral ischemia.
Using the method of transient MCAO we induced a 90 min focal cerebral ischemia in the right cerebral hemisphere of animals from the “stroke group”, while the “sham” animals underwent only a superficial skin surgery. Then performing immunohistological, fluorescent, molecular and proteinbiochemical methods we were able to show significant differences.
First, we found that there was an upregulation of AT2 receptor expression in the ischemic brain hemisphere, especially in the striatum, cerebral frontal cortex, piriform cortex and hippocampus.
Second, the AT2 receptors were expressed exclusively in neurons. In our immunofluorescent stainings we were able to prove that the striatal AT2 receptor positive cells had long neurites and co-expressed MAP2 in contrast to other AT2 receptor positive neurons away from the periinfarct area.
Third, there was no significant change in the expression of AT1 receptor between stroke and sham animals. Interestingly, many of the AT1 receptors were located in astrocytes and only sparsely in cortical neurons, which coincided with the in vitro results of Sumners et al. Many of the astrocytes in the periinfarct area appeared stouter, had powerful projections and were located around neuron-like cells. These „activated” astrocytes were significantly increased in number in both hemispheres when compared to the sham group (p<0.001), especially in the right hemisphere (p<0.0001). A lot of the activated astrocytes were also positive for the apoptotic marker cCasp-3, which is quite understandable, knowing that astrocytes are highly sensitive to ischemia.
The significant reactive astrogliosis is supposed to have both injurious and beneficial effects on neurons. Because of the AT1 receptor localization in astrocytes, we think that the AT1 receptor could be closely related with the processes of apoptosis and inflammation. We were not able to find any co-localisation of AT1 receptor with cCasp-3 but since ischemia and apoptosis are strongly dynamic processes, further detailed studies are needed to exclude or prove such an interaction.
Furthermore, we think that the expression of AT2 receptors in neurons is a sign of the previously in vitro suspected neuroprotective effect of the AT2 receptors. We found no co-expression of the AT2 receptor and markers of inflammation (ED1 and CD11b) but we still have to study the co-expression of the AT2- receptor and markers of apoptosis. Bearing in mind the positive results of AT1 antagonists in patients with cerebral ischemia, it appears possible that the surplus of angiotensin during AT1 receptor blockade activates the AT2 receptors, which leads to neuronal regeneration and growth. Of course, because of the AT1 receptor localization in astrocytes, and astrocytes being known for having both harmful and beneficial effects, it is possible that direct inhibition of the AT1 receptor itself induces reduction of apoptosis. Certainly, a combination of both effects is also possible. What will be then the role of the AT2 receptor, if it co-localises with cCasp-3?
To conclude, we were able to throw new light on the importance of the AT2 receptor expression in the brain. Our experiments demonstrate a clear upregulation of AT2 receptor expression in neurons of ischemic brain and seemed to promote neuronal survival and neurite outgrowth, and thus support a better neurological outcome, a result, which coincided well with in vitro studies. This finding offers a good explanation for the positive effect of ARBs on reducing ischemic injury and improving neurological deficits. In contrast, the AT1 receptors were not upregulated and were located predominantly in perivascular astrocytes. There was a marked increase of reactive astrocytes in the periinfarct area. In the constellation of obvious reactive astrogliosis and initiated apoptosis, it is possible that these two processes are influenced by AT1 receptor expression.
We once again realized that brain damage and brain repair is a complex and dynamic process, where the collaboration between neurons and astrocytes plays an important role, and where the decision to live or die (apoptosis versus regeneration) run on a thin line. Further experiments using a selective AT1 receptor antagonist and/or AT2 receptor antagonist as well as an agonist are needed to further clarify the interactions between neurons, astrocytes, inflammatory cells and the AT1 / AT2 receptor expression. Further new insights in the signaling mechanism that take place in the neuronal and glial cells via the AT1– and AT2 receptors responsible for the neuroprotective effects will grant the medical world to possibility to treat patients effectively and quickly, and even to offer preventive therapy.
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Fachbereich/EinrichtungMedizinische Fakultät Charité - Universitätsmedizin Berlin
Erscheinungsjahr2015
Dokumententyp/-SammlungenDissertation
Medientyp/FormatText
SpracheEnglisch
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Tag der Disputation30.05.2015
Erstellt am12.05.2015 - 07:43:40
Letzte Änderung12.05.2015 - 07:45:31
 
Statische URLhttp://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000098454
URNurn:nbn:de:kobv:188-fudissthesis000000098454-8
Zugriffsstatistik
E-Mail-Adressenadejda.gerova@charite.de