Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela; Spain. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
Aging Dis. 2011 Jun;2(3):257-74. Epub 2011 Apr 20.
For years, the renin-angiotensin system (RAS) was described as a circulating humoral system that regulates blood pressure and water homeostasis. Angiotensin II (AII) is the most important effector peptide. However, in addition to the "classical" humoral RAS there exist local RAS in many tissues and locally formed AII activates NADPH-dependent oxidases, which are a major source of superoxide and are upregulated in major aging-related diseases such as hypertension, diabetes and atherosclerosis. Accordingly, disruption of AII receptors promotes longevity in mice. The brain has an independent local RAS, which was also initially associated with the central control of blood pressure. However, more recent studies have involved brain RAS in brain disorders, including neurodegenerative diseases. The interaction between AII and dopamine is particularly interesting. Recent evidence suggests that dopamine and AII systems directly counterregulate each other in renal cells as well as in the striatum and substantia nigra. Dopamine depletion may induce RAS upregulation as a potential compensatory mechanism. However, RAS hyperactivation also exacerbates NADPH-oxidase activity, oxidative stress and the microglial inflammatory response and contribute to progression of dopaminergic neuron loss, as observed in recent studies with animal models of Parkinson's disease (PD). Aging is the most prominent risk factor for PD and other neurodegenerative diseases. Interestingly, we observed increased activation of the NADPH oxidase complex and increased levels of the pro-inflammatory cytokines in the nigra of aged male rats, which was associated with increased RAS activity and was reduced by treatment with AII antagonists. We also observed that the lack of oestrogen may act as an additional factor for increasing RAS activity in the nigra in aged females, which was significantly reduced by treatment with AII antagonists. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against the aging-related risk of dopaminergic degeneration.
多年来，肾素-血管紧张素系统 (RAS) 被描述为一种调节血压和水稳态的循环体液系统。血管紧张素 II (AII) 是最重要的效应肽。然而，除了“经典”的体液 RAS 外，许多组织中还存在局部 RAS，局部形成的 AII 激活 NADPH 依赖性氧化酶，后者是超氧化物的主要来源，并且在高血压、糖尿病和动脉粥样硬化等与衰老相关的主要疾病中上调。因此，破坏 AII 受体可促进小鼠的长寿。大脑具有独立的局部 RAS，最初也与血压的中枢控制有关。然而，最近的研究涉及大脑 RAS 与大脑疾病有关，包括神经退行性疾病。AII 和多巴胺之间的相互作用尤其有趣。最近的证据表明，多巴胺和 AII 系统在肾细胞以及纹状体和黑质中直接相互拮抗。多巴胺耗竭可能会诱导 RAS 上调作为一种潜在的补偿机制。然而，RAS 过度激活也会加剧 NADPH 氧化酶活性、氧化应激和小胶质细胞炎症反应，并导致多巴胺能神经元丢失的进展，如最近对帕金森病 (PD) 动物模型的研究所示。衰老 是 PD 和其他神经退行性疾病的最显著危险因素。有趣的是，我们观察到老年雄性大鼠黑质中 NADPH 氧化酶复合物的活性增加和促炎细胞因子水平升高，这与 RAS 活性增加有关，并通过 AII 拮抗剂治疗得到降低。我们还观察到，雌激素缺乏可能是老年雌性黑质中 RAS 活性增加的另一个因素，用 AII 拮抗剂治疗可显著降低。对大脑 RAS 的操纵可能构成一种有效的神经保护策略，以对抗与衰老相关的多巴胺能退化风险。
