Molecular Basis of the Brain Renin Angiotensin System in Cardiovascular and Neurologic Disorders: Uncovering a Key Role for the Astroglial Angiotensin Type 1 Receptor AT1R

Abstract

The central renin angiotensin system (RAS) is one of the most widely investigated cardiovascular systems in the brain. It is implicated in a myriad of cardiovascular diseases. However, studies from the last decade have identified its involvement in several neurologic abnormalities. Understanding the molecular functionality of the various RAS components can thus provide considerable insight into the phenotypic differences and mechanistic drivers of not just cardiovascular but also neurologic disorders. Since activation of one of its primary receptors, the angiotensin type 1 receptor (AT1R), results in an augmentation of oxidative stress and inflammatory cytokines, it becomes essential to investigate not just neuronal RAS but glial RAS as well. Glial cells are key homeostatic regulators in the brain and are critical players in the resolution of overt oxidative stress and neuroinflammation. Designing better and effective therapeutic strategies that target the brain RAS could well hinge on understanding the molecular basis of both neuronal and glial RAS. This review provides a comprehensive overview of the major studies that have investigated the mechanisms and regulation of the brain RAS, and it also provides insight into the potential role of glial AT1Rs in the pathophysiology of cardiovascular and neurologic disorders.

The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling

“…Renin-angiotensin system (RAS) is originally acknowledged for its role in the regulation of blood pressure, but now it is generally accepted that brain has its intrinsic RAS with the major components, including angiotensin converting enzyme (ACE) and angiotensin II (Ang II) receptor type 1 (AT1), widely distributed in the central nervous system (Haspula and Clark, 2018; Uijl et al, 2018). The brain RAS actively participates in various neurological functions, including cognition, memory, emotion and stress response, and RAS over-activation has been identified in several neuropsychiatric disorders, including Alzheimer’s disease, epilepsy and depression (Yagi et al, 2013; Gebre et al, 2018).…”

Prolonged Bat Call Exposure Induces a Broad Transcriptional Response in the Male Fall Armyworm (Spodoptera frugiperda; Lepidoptera: Noctuidae) Brain

“…Manual analysis of the KEGG pathway reconstruction of DE transcripts revealed a variety of interconnected neuron-specific metabolic and signaling cascades that were affected by bat ultrasound exposure, including the mechanistic target of rapamycin (mTOR)/Akt, MAPK, Wnt, prolactin, Hippo, and calcium signaling systems, and associated regulatory responses, such as p53, renin-angiotensin, and NF-κB transcript expression. Notably, recent research on the conserved function of these biochemical pathways in the nervous systems of metazoan taxa across phyla describes the function and biological relevance of these pathways on an organismal scale (Mattson and Camandola, 2001; Lilienbaum and Israe, 2003; Pan, 2007; Lau and Bading, 2009; Tedeschi and Di Giovanni, 2009; Brown et al, 2012; Lin et al, 2012; Graber et al, 2013; Flentke et al, 2014; Mao et al, 2014; Patil et al, 2014; Layden et al, 2016; Guo et al, 2017; Haspula and Clark, 2018). For instance, synaptic glutamate (Sinakevitch et al, 2010; Thomas and Sigrist, 2012; Li et al, 2016), mTOR/Akt (Guo et al, 2017), intracellular calcium (Kaltschmidt et al, 2005; Lau and Bading, 2009), and prolactin signaling (Brown et al, 2012; Belugin et al, 2013), followed by differential p53 and NF-κB transcription (Kaltschmidt et al, 2005; Lau and Bading, 2009) are each implicated in the apoptotic and synaptic-activity mediated induction of neural plasticity, learning, and memory from diverse taxa spanning arthropods to chordates.…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…A detailed understanding of the molecular signaling of central and peripheral AT1Rs in pathophysiology and possible crosstalk with CB1R, is beyond the scope of this review. Please refer to reviews from Haspula and Clark [ 147 ] and Forrester et al [ 148 ] for a better understanding of the AT1R signaling mechanisms.…”