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Title: | Angiotensin AT1 and AT2 receptors heteromer expression in microglia correlates with Parkinson's disease progression in the hemilesioned rat model of the disease |
Author: | Rivas‐Santisteban, Rafael Rodríguez Pérez, Ana I. Muñoz, Ana Reyes Resina, Irene Labandeira García, José L. Navarro Brugal, Gemma Franco Fernández, Rafael |
Keywords: | Receptors cel·lulars Malaltia de Parkinson Malalties neurodegeneratives Cell receptors Parkinson's disease Neurodegenerative Diseases |
Issue Date: | 1-Feb-2020 |
Publisher: | Karger |
Abstract: | Background/Aims : The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy, using the precursor levodopa, leads to dyskinesias as the main side effect. Angiotensin AT 1 and AT 2 receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT 1/2 Hets), are present in the central nervous system. We assessed the functionality and expression of AT 1/2 Hets in Parkinson Disease (PD). Methods: Immunocytochemistry was used to analyze the colocalization between angiotensin receptors, bioluminescence resonance energy transfer was used to detect AT 1/2 Hets. Calcium and cAMP determination, MAPK activation and label-free assays were performed to characterize signaling. Proximity ligation assays was used to quantify receptor expression in microglial cells and brain striatal slices. Results: We confirmed that AT 1 and AT 2 receptors form AT 1/2 Hets that are expressed in cells of the central nervous system. AT 1/2 Hets are novel functional units with particular signaling properties. Importantly, the coactivation of the two receptors in the heteromer reduces the signaling output of angiotensin. Remarkably, AT 1/2 Hets that are expressed in both striatal neurons and microglia show a cross-potentiation, i.e. candesartan, the antagonist of AT 1 increases the effect of AT 2 receptor agonists. In addition, the level of expression in the unilateral 6-OH-dopamine lesion rat PD model increases upon disease progression and is maximal in dyskinetic animals. Conclusion: The results indicate that boosting the action of neuroprotective AT 2 receptors using an AT 1 receptor antagonist constitutes a promising therapeutic strategy in PD. |
Note: | Reproducció del document publicat a: |
It is part of: | Cellular Physiology and Biochemistry, 2020 |
URI: | http://hdl.handle.net/2445/175330 |
ISSN: | 1015-8987 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) Articles publicats en revistes (Bioquímica i Fisiologia) |
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