Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación en Red, enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain.
J Neuroinflammation. 2020 Aug 17;17(1):243. doi: 10.1186/s12974-020-01908-z.
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 and AT receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (ATHets), are present in the central nervous system. We assessed the functionality and expression of ATHets in Parkinson disease (PD).
Immunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect ATHets. 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.
We confirmed that AT and AT receptors form ATHets that are expressed in cells of the central nervous system. ATHets 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, ATHets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT, increases the effect of AT 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.
The results indicate that boosting the action of neuroprotective AT receptors using an AT receptor antagonist constitutes a promising therapeutic strategy in PD.
背景/目的：肾素-血管紧张素系统（RAS）在帕金森病（PD）中发生改变，这是一种由于黑质神经元变性引起的疾病，其多巴胺替代疗法使用前体左旋多巴，导致运动障碍作为主要副作用。血管紧张素 AT 和 AT 受体，主要因其在调节水稳态和血压方面的作用而闻名，并能够形成异源二聚体（ATHets），存在于中枢神经系统中。我们评估了 ATHets 在帕金森病（PD）中的功能和表达。
免疫细胞化学用于分析血管紧张素受体的共定位；生物发光共振能量转移用于检测 ATHets。钙和 cAMP 测定、MAPK 激活和无标记测定用于表征同源和异源系统中的信号转导。接近连接测定用于定量小鼠原代培养物和大鼠纹状体切片中的受体表达。
我们证实 AT 和 AT 受体形成 ATHets，存在于中枢神经系统的细胞中。ATHets 是具有特殊信号特性的新型功能单位。重要的是，异源二聚体中两个受体的共激活降低了血管紧张素的信号输出。值得注意的是，在纹状体神经元和小胶质细胞中表达的 ATHets 使得 AT 的拮抗剂坎地沙坦能够增加 AT 受体激动剂的作用。此外，与出现运动障碍的动物相比，单侧 6-羟多巴胺损伤的 PD 模型大鼠纹状体的表达水平增加，并且在慢性给予左旋多巴后不会出现运动障碍的帕金森样动物中的表达水平明显更高。
结果表明，使用 AT 受体拮抗剂增强神经保护 AT 受体的作用是 PD 的一种有前途的治疗策略。
