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Current understanding of the origin of brain renin-angiotensin system (RAS) components. Circulating renin, prorenin, and angiotensinogen (Agt) are unlikely to pass the blood-brain barrier (BBB). Intracellular (i.c.) renin does not contribute to brain RAS activity. Agt has been shown in brain cells and cerebrospinal fluid, yet whether actual release from cells into cerebrospinal fluid occurs remains unclear, nor do we know how brain cell-derived Agt contributes to local angiotensin (Ang) generation in the absence of renin. Circulating Ang II may bind to brain Ang II type 1 or 2 (AT1, AT2) receptors (R) outside the BBB, or could diffuse into the brain under conditions where the BBB is disturbed (right part of the figure), like in hypertension. Possibly, such diffusion results in local formation of Ang-(1-7) and subsequent Mas receptor stimulation
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Purpose of Review
Although an independent brain renin-angiotensin system is often assumed to exist, evidence for this concept is weak. Most importantly, renin is lacking in the brain, and both brain angiotensinogen and angiotensin (Ang) II levels are exceptionally low. In fact, brain Ang II levels may well represent uptake of circulating Ang II via...
Citations
... 38,39 Besides, brain angiotensinogen is not correlated with the circulating one. 40 It has been shown that 90% of brain angiotensinogen is mainly produced by astrocytes and little from neurons and glial cells. 41 In addition, components of RAS as well as pro-renin are also expressed in the basal ganglion, mainly in the nigrostriatal pathway. ...
Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.
... 41 A more simple explanation is that brain Ang II is taken up from blood. 42 Interestingly, despite the absence of a blood pressure-lowering effect, AGT siRNA did Clearly, such formation also depends on hepatic AGT. 43,44 In the SHR, the degree of blood pressure lowering by AGT siRNA was similar to that of classical RAS blockers including ACE (angiotensin-converting enzyme) inhibitors and ARBs (AT 1 receptor blockers), while combining GalNAc-AGT siRNA and an ARB resulted in synergistic and superior blood pressure lowering (≈70 versus ≈20-25 mm Hg for each drug separately). ...
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N -acetylgalactosamine ligand–conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides.
... The renin-angiotensin system (RAS) is a central regulator of cardiovascular and renal functions and plays a key role in the pathophysiology of various diseases. The classical RAS consists of a series of enzymatic reactions begins from angiotensinogen (AGT; 485 amino acids) and concluding in the generation of ACE mediated vasoconstrictor peptide angiotensin II (Ang-II; 'Asp-Arg-Val-Tyr-Ile-His-Pro-Phe') in plasma as well as in various tissues including the heart, kidneys, lungs, brain (Fyhrquist and Saijonmaa, 2008;Ren et al., 2019). This angiotensin II is reported to play a very crucial role in various RAS related human pathophysiology mainly belongs to cardiovascular and renal diseases, i.e., hypertension, heart failure, blood pressure, peripheral vascular disease (Ferrario et al., 1989;Kurdi et al., 2005). ...
COVID-19, caused by zoonotic coronavirus SARS-CoV-2, is not a first coronavirus infection, prior to this,
two severe coronavirus infections were already faced by the humans at different parts of the world. COVID-19
is found to be more severe than its previous counterparts and cause respiratory syndrome along with some
other pathophysiology effects. The main human protein which used by SARS causing coronavirus
(SARS-CoV and SARS-CoV-2) is angiotensin-converting enzyme 2 (ACE2), a key member and regulator of
RAS. Coronavirus shows a significant affinity with the ACE2, spike protein of the virus participate in this
crucial interaction and initiate the infection cycle of the SARS. This ACE2 plays a very significant role in RAS,
which directly affect the pathophysiology of humans, mainly of respiratory and cardiovascular diseases.
Blockage or down-regulation of ACE2 can easily block the virus entry in the cells, but due to the other
important role of the ACE2, the human system cannot afford its suppression or blockage. Due to its
importance, it is required to understand the physiology and pathophysiological role of the ACE2, which can
help to develop therapy against the SARS. This report provides a detailed account of ACE2, and help to
understand about it, which will help to plan a possible way to fight against SARS-CoV-2 and other
coronaviruses.
... Renin is produced in the specialized kidney granular cells called juxtaglomerular (JG) in its 406 amino acid-long precursor named prorenin. In response to the JG cell activation due to low arterial BP, low sodium chloride, or sympathetic nervous system activity, prorenin is converted to renin by which in the bloodstream, it acts on its target, angiotensinogen, and cleaves angiotensinogen into angiotensin I [57,58]. In the vascular endothelium of the lungs and kidney, the decapeptide angiotensin I is further converted by the endothelial-bound angiotensin-converting enzyme (ACE) into an octapeptide hormone angiotensin II, a potent vasoconstrictor and the primary active product of the RAAS [55,59]. ...
Hypertension is a multifactorial disease due to a complex interaction among genetic, epigenetic, and environmental factors. Characterized by raised blood pressure (BP), it is responsible for more than 7 million deaths per annum by acting as a leading preventable risk factor for cardiovascular disease. Reports suggest that genetic factors are estimated to be involved in approximately 30 to 50% of BP variation, and epigenetic marks are known to contribute to the initiation of the disease by influencing gene expression. Consequently, elucidating the genetic and epigenetic mediators associated with hypertension is essential for better discernment of its pathophysiology. By deciphering the unprecedented molecular hypertension basis, it could help to unravel an individual’s inclination towards hypertension which eventually could result in an arrangement of potential strategies for prevention and therapy. In the present review, we discuss known genetic and epigenetic drivers that contributed to the hypertension development and summarize the novel variants that have currently been identified. The effect of these molecular alterations on endothelial function was also presented.
... The cascade starts from the production of renin by the activation of the juxtaglomerular cells in the afferent arterioles of the kidney, thereby cleaving the inactive prorenin to renin. These cells are activated when there is a reduction in blood pressure, beta-activation, or when macula densa cells detect a decreased sodium load in the distal convoluted tubule [27,28]. Upon release into the bloodstream, renin targets angiotensinogen in the plasma. ...
Heart failure (HF), which is a major clinical and public health challenge, commonly develops when the myocardial muscle is unable to pump an adequate amount of blood at typical cardiac pressures to fulfill the body’s metabolic needs, and compensatory mechanisms are compromised or fail to adjust. Treatments consist of targeting the maladaptive response of the neurohormonal system, thereby decreasing symptoms by relieving congestion. Sodium–glucose co-transporter 2 (SGLT2) inhibitors, which are a recent antihyperglycemic drug, have been found to significantly improve HF complications and mortality. They act through many pleiotropic effects, and show better improvements compared to others existing pharmacological therapies. Mathematical modeling is a tool used to describe the pathophysiological processes of the disease, quantify clinically relevant outcomes in response to therapies, and provide a predictive framework to improve therapeutic scheduling and strategies. In this review, we describe the pathophysiology of HF, its treatment, and how an integrated mathematical model of the cardiorenal system was built to capture body fluid and solute homeostasis. We also provide insights into sex-specific differences between males and females, thereby encouraging the development of more effective sex-based therapies in the case of heart failure.
... However, in most brain regions, including the frontal and temporal lobes that are associated with AD pathology, a fully formed BBB prevents the influx of circulatory Ang-II into the tissue and therefore presumably relies solely on RAS components synthesised within the brain tissue. There is evidence that most RAS components are expressed locally within the brain and can therefore function independently from circulating RAS although there is still debate as to whether renin, responsible for the conversion of angiotensinogen into angiotensin I, is expressed locally or derived systemically [14]. ...
An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer’s disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline.
Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1–7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD – 2, 6, and 12 months of age; Apd9 – 3-4, 12, and 18 months of age; Tg2576 – 3-4 and 24 months of age; and PDAPP – 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls.
ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age.
These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aβ, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aβ deposition.
... In this study, we have measured the key downstream RAS mediating enzymes (ACE-1 and ACE-2, respectively) and Ang-II levels (as a key determinant of prevailing signaling routes in counter-regulatory RAS pathways following conversion to Ang- [1][2][3][4][5][6][7] or Ang-III/Ang-IV) in the FCx and temporal cortex (TCx) in a cohort of normal aging and a separate AD and age-matched control cohort that was grouped according to disease stage severity: controls (Braak tangle stage 0-II), intermediate stage (Braak tangle stage III-IV), and end-stage disease (Braak tangle stage V-VI). We hypothesized that an age-related imbalance in brain ACE-1 and ACE-2 activity is exacerbated in the early stages of AD in association with disease pathology in AD. ...
... It remains unclear whether renin, responsible for the conversion of angiotensinogen to angiotensin-I, is expressed locally within the brain. A recent study indicated that most brain renin originates in the bloodstream (3). Chymases, such as tonin and cathepsin D can produce angiotensin-I independently of renin within the brain (25,26). ...
An imbalance in the renin-angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer’s disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n=121) (19-95y age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, UK, and AD and age-matched controls (n=60) from the South West Dementia Brain Bank, University of Bristol, UK, stratified according to Braak tangle stage (BS): 0-II, III-IV (intermediate disease) and V-VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and angiotensin-II (Ang-II) protein level was measured by ELISA. In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal ageing. ACE-1 enzyme activity was elevated at an early/intermediate stage i.e. BS III-IV compared to BS 0-II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.
... While the latter is released constitutively in its inactive form, activation of JG cells causes the cleavage of prorenin to renin. Once these cells are active, blood pressure drops, betaactivation occurs, and macula densa cells become activated in response to a lower sodium load in the distal convoluted tubule [102,103]. ...
The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its down-regulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
... The process of renin secretion is regulated by the stretch receptors of the vascular wall, dense plaque receptors, and sympathetic nerves [27,28]. The stretch sensor can sense changes in renal blood flow. ...
... CKD is a pathological condition associated with an unexplained decrease in the glomerular filtration rate (GFR) (<0.06 L/min) for more than three months. Due to reduced renal blood flow and GFR, the stretch receptors of the arteriolar artery and dense plaques are excited, renin secretion increases, and the RAAS is subsequently activated [27,28]. Under the combined action of Ang II and Ang III, the stability of renal blood flow and the GFR are maintained [31]. ...
Cardiorenal syndrome (CRS), a clinical syndrome involving multiple pathological mechanisms, exhibits high morbidity and mortality. According to the primary activity of the disease, CRS can be divided into cardiorenal syndrome (type I and type II), renal heart syndrome (type III and type IV), and secondary heart and kidney disease (type V). The renin-angiotensin-aldosterone system (RAAS) is an important humoral regulatory system of the body that exists widely in various tissues and organs. As a compensatory mechanism, the RAAS is typically activated to participate in the regulation of target organ function. RAAS activation plays a key role in the pathogenesis of CRS. The RAAS induces the onset and development of CRS by mediating oxidative stress, uremic toxin overload, and asymmetric dimethylarginine production. Research on the mechanism of RAAS-induced CRS can provide multiple intervention methods that are of great significance for reducing end-stage organ damage and further improving the quality of life of patients with CRS.
... The renin-angiotensin system (RAS) encompasses a complex and wide network of enzymes, peptides, and receptors (Fig. 3) that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance [39]. Reduction of renal blood flow stimulates the conversion of prorenin to rennin by juxtaglomerular cells in the kidneys. ...
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a highly pathogenic member of family coronaviridae, has caused an exponentially growing global pandemic termed as the coronavirus disease 2019 (COVID-19) with more than 12 million cases worldwide till date. This deadly disease has average fatality rate of 6.5% and even higher among elderly patients and patients with comorbidities. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE-2) as the entry receptor into host cell. ACE-2, a type-I transmembrane metallocarboxypeptidase, is a critical regulator of the renin-angiotensin system. The entry of SARS-CoV-2 within host cells results in a reduced availability of ACE-2 on the host cell surface followed by significant downregulation of ACE-2 gene expression. As ACE-2 is a well-known cardio-protective molecule, its downregulation could result in severe cardiac disorders. This review deals with a challenging aspect of SARS-CoV-2 infected patients who are asymptomatic or have mild syndromes similar to influenza infections. These patients are proving to be the Achilles’ heel to combat COVID-19 mainly in developing countries of South Asia, where the average number of tests conducted per million individuals is considerably low. Consequently, there is high possibility that individuals with negligible respiratory trouble will not be tested for SARS-CoV-2. Hence, a huge percentage of the population have the risk of developing cardiovascular disorders as a bystander effect of viral infection apart from being potential reservoir of disease transmission. Based on available demographic as well as molecular data, this review predicts a huge spike in cardiovascular disorders among this undetected reservoir in post COVID-19 era.
