IMR Press / FBL / Volume 26 / Issue 9 / DOI: 10.52586/4972
Open Access Review
The renin-angiotensin system in central nervous system tumors and degenerative diseases
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1 Department of Neurosurgery, Wellington Regional Hospital, 6242 Wellington, New Zealand
2 Gillies McIndoe Research Institute, 6242 Wellington, New Zealand
3 Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, 3050 Victoria, Australia
4 Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, 3050 Victoria, Australia
5 Department of Neurosurgery, Hadassah Hebrew University Medical Centre, 91120 Jerusalem, Israel
6 Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, 5040 Lower Hutt, New Zealand
*Correspondence: (Agadha C Wickremesekera); (Swee T Tan)
These authors contributed equally.
Front. Biosci. (Landmark Ed) 2021, 26(9), 628–642;
Submitted: 12 July 2021 | Revised: 10 August 2021 | Accepted: 16 August 2021 | Published: 30 September 2021
Copyright: © 2021 The Author(s). Published by BRI.
This is an open access article under the CC BY 4.0 license (

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 (AT1R), ATII receptor 2 (AT2R) 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 AT1R and AT2R through two competitive arms: an ACE1/ATII/AT1R axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/AT2R 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/AT1R 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.

Central nervous system
Renin-angiotensin system
Parkinson’s disease
Cerebral organoids
Fig. 1.
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