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01-12-2020 | Parkinson's Disease | Research

Angiotensin AT₁ and AT₂ receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia

Authors: Rafael Rivas-Santisteban, Ana I. Rodriguez-Perez, Ana Muñoz, Irene Reyes-Resina, José Luis Labandeira-García, Gemma Navarro, Rafael Franco

Published in: Journal of Neuroinflammation | Issue 1/2020

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 AT₁ and AT₂ receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT_1/2Hets), are present in the central nervous system. We assessed the functionality and expression of AT_1/2Hets in Parkinson disease (PD).

Methods

Immunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect AT_1/2Hets. Calcium and cAMP determination, MAPK activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections.

Results

We confirmed that AT₁ and AT₂ receptors form AT_1/2Hets that are expressed in cells of the central nervous system. AT_1/2Hets 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_1/2Hets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT₁, increases the effect of AT₂ receptor agonists. In addition, the level of striatal expression increased in the unilateral 6-OH-dopamine lesioned rat PD model and was markedly higher in parkinsonian-like animals that did not become dyskinetic upon levodopa chronic administration if compared with expression in those that became dyskinetic.

Conclusion

The results indicate that boosting the action of neuroprotective AT₂ receptors using an AT₁ receptor antagonist constitutes a promising therapeutic strategy in PD.

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Title: Angiotensin AT1 and AT2 receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia
Authors: Rafael Rivas-Santisteban
Ana I. Rodriguez-Perez
Ana Muñoz
Irene Reyes-Resina
José Luis Labandeira-García
Gemma Navarro
Rafael Franco
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Parkinson's Disease
Candesartan
Levodopa
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01908-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Angiotensin AT₁ and AT₂ receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia

Abstract

Background/aims

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background/aims

Methods

Results

Conclusion

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