Within the Brain: The Renin Angiotensin System

Abstract

For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial.

Keywords: aging; alzhemiers disease (AD); angiotensin; angiotensin AT1 receptor; angiotensin AT2 receptor; inflammation; mas receptor; mas-related-G protein coupled MrgD receptor; microglia; parkinson’s disease (PD); vascular cognitive impairment (VCI).

Figure 1

Schematic Diagram Depicting The RAS Components Within The Brain. Various brain cells possess different members of the RAS system which allows for the local synthesis and biological actions of angiotensin in the brain. The legend indicates the cells depicted within each illustration (astrocytes, neurons, and microglia). Enzymes convert precursor angiotensin fragments into neuroactive forms. Enzymes are indicated by circles. Neuroactive forms include: Angiotensins II, III, IV, (1–7), and Alamandine. The main biologically active forms are indicated with colored amino acid sequences. Abbreviations: angiotensin-converting enzyme (ACE) and (ACE2), aminopeptidase A (AP–A), aminopeptidase N (AP–N), neutral endopeptidase (NEP), decarboxylase (DC).

Figure 2

Schematic Diagram Depicting Neuronal Plasma Membrane and Intracellular RAS Signaling. Angiotensins II, IV, (1–7), and Alamandine are the main neuroactive forms and their signaling is indicated by arrows leading to their receptors. Receptors can form heterodimers. In the case of the MasR/AT2R heterodimer, arrows leading to the receptor from its ligands indicate its functionality. The AT2R/AT1R and MasR/AT1R heterodimers are inactive, indicated by an absence of arrows. Angiotensin (1–7) binds MasRs with the highest affinity, but can also bind AT2Rs and MrgDs. Angiotensin II binds AT1Rs and AT2Rs with the highest affinity. Alamandine binds MrgDs with the highest affinity. Angiotensin IV binds AT4Rs with the highest affinity, but can also bind AT1Rs. Angiotensin III is not depicted here since it is not a main neuroactive peptide, it binds AT2Rs with the highest affinity, but can also bind AT1Rs. Receptors can be located on the plasma membrane or intracellularly. Intracellular locations include the nucleus, mitochondria and neurosecretory vesicles. Therapeutics such as Angiotensin II type I receptor blockers (ARBs) and the AT2R agonist, Compound 21 (C21) can be used to modulate receptor signaling.

Figure 3

Schematic Representation of The Biological Actions of The RAS System In The Brain. Ras Components And Their Cognate Receptors Are Depicted In The Figure Key. Under physiological conditions, RAS components such as Ang (1–7), Ang II and Ang IV and their cognate receptors MasR, AT2R and AT4R that mediate beneficial effects to improve cognition are in abundance in different cell types depicted in the table. In conditions such as aging, and disease states such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Vascular Cognitive Impairment (VCI) and Post-Stroke Cognitive Impairment (PSCI), Ang II/AT1R axis predominates and exacerbates the development of cognitive impairment, depicted by the seesaw.