Role of the renin-angiotensin system in the development of COVID-19-associated neurological manifestations

Abstract

SARS-CoV-2 causes COVID-19, which has claimed millions of lives. This virus can infect various cells and tissues, including the brain, for which numerous neurological symptoms have been reported, ranging from mild and non-life-threatening (e.g., headaches, anosmia, dysgeusia, and disorientation) to severe and life-threatening symptoms (e.g., meningitis, ischemic stroke, and cerebral thrombosis). The cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), an enzyme that belongs to the renin-angiotensin system (RAS). RAS is an endocrine system that has been classically associated with regulating blood pressure and fluid and electrolyte balance; however, it is also involved in promoting inflammation, proliferation, fibrogenesis, and lipogenesis. Two pathways constitute the RAS with counter-balancing effects, which is the key to its regulation. The first axis (classical) is composed of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and angiotensin type 1 receptor (AT1R) as the main effector, which -when activated- increases the production of aldosterone and antidiuretic hormone, sympathetic nervous system tone, blood pressure, vasoconstriction, fibrosis, inflammation, and reactive oxygen species (ROS) production. Both systemic and local classical RAS' within the brain are associated with cognitive impairment, cell death, and inflammation. The second axis (non-classical or alternative) includes ACE2, which converts Ang II to Ang-(1-7), a peptide molecule that activates Mas receptor (MasR) in charge of opposing Ang II/AT1R actions. Thus, the alternative RAS axis enhances cognition, synaptic remodeling, cell survival, cell signal transmission, and antioxidant/anti-inflammatory mechanisms in the brain. In a physiological state, both RAS axes remain balanced. However, some factors can dysregulate systemic and local RAS arms. The binding of SARS-CoV-2 to ACE2 causes the internalization and degradation of this enzyme, reducing its activity, and disrupting the balance of systemic and local RAS, which partially explain the appearance of some of the neurological symptoms associated with COVID-19. Therefore, this review aims to analyze the role of RAS in the development of the neurological effects due to SARS-CoV-2 infection. Moreover, we will discuss the RAS-molecular targets that could be used for therapeutic purposes to treat the short and long-term neurological COVID-19-related sequelae.

Keywords: ACE2; COVID-19; SARS-CoV-2; long COVID; neuroinflammation; neurological manifestations; renin-angiotensin system.

FIGURE 1

Renin-Angiotensin-System in the brain. The cleavage of cerebral angiotensinogen produces four main neuroactive peptides: Ang II, Ang IV, Ang-(1-7), and alamandine. The upregulation of ACE leads to the hyperactivation of AT1R by Ang II conducing to brain vasoconstriction associated with cognitive impairment, cell death, and inflammation. In contrast, the binding of Ang II to AT2R, the bind of Ang IV, Ang-(1-7), and alamandine to AT4R, MasR, and MrgDR respectively, are related to enhancing cognition, synaptic remodeling, cell survival, cell signal transmission, and antioxidant/anti-inflammatory mechanisms leading to improvement of cognition.

FIGURE 2

Neurological symptoms as consequence of classical RAS upregulation in COVID-19 patients. The lack of Ang II processing by ACE2 and its subsequent binding to AT1R can cause a local pro-inflammatory state that activates neuronal programmed cell death and the consequent dopaminergic neuronal loss leading to cognitive problems. Accumulating evidence indicates that brain areas unaffected by the virus show a low AT1R expression accompanied by high AT2R expression. Then, Ang II can bind to AT2R with high affinity, triggering protective mechanisms such as neuronal survival. Although previous information suggested that peripheral sensory neurons did not express ACE2, recent evidence indicates that these cells express low ACE2 levels, which may favor viral entry and infection. Subsequently, the infection leads to altered expression of genes associated with chemosensory functions, such as the olfactory neuronal markers, fibronectin leucine-rich transmembrane protein (FLRT3), drebrin 1 (DBN1), taste 2 receptor member 31 (TAS2R31), chemosensory regulatory factors Yin Yang 1 (YY1), and cannabinoid receptor 1 (CNR1). Moreover, the musculoskeletal symptoms in COVID-19 patients could be related to Ang II upregulation that orchestrates protein degradation and skeletal muscle cell apoptosis, possibly leading to loss of skeletal muscle fibers.

FIGURE 3

RAS-mediated therapeutic approaches against SARS-CoV-2 infection. The therapeutic approaches involve using ARBs (Angiotensin II receptor blockers) to inhibit the binding of Ang II to AT1R (red lines) or virus entry blocking by using the ACE2 soluble form or embedded in nanoparticles.