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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/175330
Angiotensin AT1 and AT2 receptors heteromer expression in microglia correlates with Parkinson's disease progression in the hemilesioned rat model of the disease
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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.
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RIVAS‐SANTISTEBAN, Rafael, RODRÍGUEZ PÉREZ, Ana i., MUÑOZ, Ana, REYES RESINA, Irene, LABANDEIRA GARCÍA, José l., NAVARRO BRUGAL, Gemma, FRANCO FERNÁNDEZ, Rafael. Angiotensin AT1 and AT2 receptors heteromer expression in microglia correlates with Parkinson's disease progression in the hemilesioned rat model of the disease. _Cellular Physiology and Biochemistry_. 2020. [consulta: 7 de febrer de 2026]. ISSN: 1015-8987. [Disponible a: https://hdl.handle.net/2445/175330]