Haron Simon, Kilmister Ethan J, Davis Paul F, Stylli Stanley S, Mantamadiotis Theo, Kaye Andrew H, Hall Sean R, Tan Swee T, Wickremesekera Agadha C
Department of Neurosurgery, Wellington Regional Hospital, 6242 Wellington, New Zealand.
Gillies McIndoe Research Institute, 6242 Wellington, New Zealand.
Front Biosci (Landmark Ed). 2021 Sep 30;26(9):628-642. doi: 10.52586/4972.
Despite their differences, central nervous system (CNS) tumors and degenerative diseases share important molecular mechanisms underlying their pathologies, due to their common anatomy. Here we review the role of the renin-angiotensin system (RAS) in CNS tumors and degenerative diseases, to highlight common molecular features and examine the potential merits in repurposing drugs that inhibit the RAS, its bypass loops, and converging signaling pathways. The RAS consists of key components, including angiotensinogen, (pro)renin receptor (PRR), angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (ATR), ATII receptor 2 (ATR) and the Mas receptor (MasR). The RAS is integral to systemic and cellular pathways that regulate blood pressure and body fluid equilibrium and cellular homeostasis. The main effector of the RAS is ATII which exerts its effect by binding to ATR and ATR through two competitive arms: an ACE1/ATII/ATR axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/ATR and/or ATII/ACE2/Ang(1-7)/MasR axis that potentiates neuroprotection pathways. Alterations of these axes are associated with cellular dysfunction linked to CNS diseases. The generation of ATII is also influenced by proteases that constitute bypass loops of the RAS. These bypass loops include cathepsins B, D and G and chymase and aminopeptidases. The RAS is also influenced by converging pathways such as the Wnt/β-catenin pathway which sits upstream of the RAS via PRR, a key component of the RAS. We also discuss the co-expression of components of the RAS and markers of pluripotency, such as OCT4 and SOX2, in Parkinson's disease and glioblastoma, and their potential influences on transduction pathways involving the Wnt/β-catenin, MAPK/ERK, PI3K/AKT and vacuolar (H) adenosine triphosphatase (V-ATPase) signaling cascades. Further research investigating modulation of the ACE1/ATII/ATR and ACE2/Ang(1-7)/MasR axes with RAS inhibitors may lead to novel treatment of CNS tumors and degenerative diseases. The aim of this review article is to discuss and highlight experimental and epidemiological evidence for the role of the RAS, its bypass loops and convergent signaling pathways in the pathogenesis of CNS tumors and degenerative diseases, to direct research that may lead to the development of novel therapy.
尽管中枢神经系统（CNS）肿瘤和退行性疾病存在差异，但由于它们共同的解剖结构，在其病理过程中共享重要的分子机制。在此，我们综述肾素-血管紧张素系统（RAS）在CNS肿瘤和退行性疾病中的作用，以突出共同的分子特征，并探讨重新利用抑制RAS、其旁路环和汇聚信号通路的药物的潜在价值。RAS由关键成分组成，包括血管紧张素原、（前）肾素受体（PRR）、血管紧张素转换酶1（ACE1）、血管紧张素转换酶2（ACE2）、血管紧张素I（ATI）、血管紧张素II（ATII）、ATII受体1（ATR）、ATII受体2（ATR）和Mas受体（MasR）。RAS是调节血压、体液平衡和细胞稳态的全身和细胞途径所不可或缺的。RAS的主要效应物是ATII，它通过两个竞争臂与ATR和ATR结合发挥作用：一个是ACE1/ATII/ATR轴，参与调节氧化应激和神经炎症途径；另一个是ATII/ATR和/或ATII/ACE2/Ang（1-7）/MasR轴，增强神经保护途径。这些轴的改变与CNS疾病相关的细胞功能障碍有关。ATII的产生也受构成RAS旁路环的蛋白酶影响。这些旁路环包括组织蛋白酶B、D和G、糜酶和氨肽酶。RAS还受汇聚信号通路影响，如Wnt/β-连环蛋白通路，它通过RAS的关键成分PRR位于RAS上游。我们还讨论了RAS成分与多能性标志物（如OCT4和SOX2）在帕金森病和胶质母细胞瘤中的共表达，以及它们对涉及Wnt/β-连环蛋白、MAPK/ERK、PI3K/AKT和液泡（H）腺苷三磷酸酶（V-ATPase）信号级联的转导途径的潜在影响。进一步研究用RAS抑制剂调节ACEI/ATII/ATR和ACE2/Ang（1-7）/MasR轴可能会带来CNS肿瘤和退行性疾病的新疗法。这篇综述文章的目的是讨论并强调RAS及其旁路环和汇聚信号通路在CNS肿瘤和退行性疾病发病机制中作用的实验和流行病学证据，以指导可能导致新疗法开发的研究。
