Brain angiotensin system: a new promise in the management of epilepsy?

Abstract Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin–angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263–2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

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Functional expression of the renin-angiotensin system in human podocytes

AJP Renal Physiology ◽

10.1152/ajprenal.00475.2004 ◽

2006 ◽

Vol 290 (3) ◽

pp. F710-F719 ◽

Cited By ~ 86

Author(s):

Max C. Liebau ◽

D. Lang ◽

J. Böhm ◽

N. Endlich ◽

Martin J. Bek ◽

...

Keyword(s):

Renin Angiotensin System ◽

Functional Expression ◽

Kidney Cortex ◽

Receptor Subtypes ◽

Ang Ii ◽

Angiotensin Receptor ◽

Angiotensin System ◽

Renin Angiotensin ◽

Beneficial Effects ◽

Glomerular Proteinuria

Experimental and clinical studies impressively demonstrate that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) significantly reduce proteinuria and retard progression of glomerular disease. The underlying intraglomerular mechanisms are not yet fully elucidated. As podocyte injury constitutes a critical step in the pathogenesis of glomerular proteinuria, beneficial effects of ACEI and ARB may partially result from interference with a local renin-angiotensin system (RAS) in podocytes. The knowledge of expression and function of a local RAS in podocytes is limited. In this study, we demonstrate functional expression of key components of the RAS in differentiated human podocytes: podocytes express mRNA for angiotensinogen, renin, ACE type 1, and the AT1 and AT2 angiotensin receptor subtypes. In Western blot experiments and immunostainings, expression of the AT1 and AT2 receptor was demonstrated both in differentiated human podocytes and in human kidney cortex. ANG II induced a concentration-dependent increase in cytosolic Ca2+ concentration via AT1 receptors in differentiated human podocytes, whereas it did not increase cAMP. Furthermore, ANG II secretion was detected, which was blocked by neither the ACEI captopril nor the renin inhibitor remikiren nor the chymase inhibitor chymostatin. ANG II secretion of podocytes was not increased by mechanical stress. Finally, ANG II was found to increase staurosporine-induced apoptosis in podocytes. We speculate that ACEI and ARB exert their beneficial effects, in part, by interfering with a local RAS in podocytes. Further experiments are required to identify the underlying molecular mechanism(s) of podocyte protection.

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Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis

Physiological Genomics ◽

10.1152/physiolgenomics.00037.2010 ◽

2010 ◽

Vol 42 (3) ◽

pp. 437-444 ◽

Cited By ~ 17

Author(s):

Micheline M. de Resende ◽

Timothy J. Stodola ◽

Andrew S. Greene

Keyword(s):

Skeletal Muscle ◽

Bone Marrow ◽

Endothelial Cell ◽

Cell Function ◽

Therapeutic Potential ◽

Renin Angiotensin System ◽

Brown Norway ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin

Autologous bone marrow cell (BMC) transplantation has been shown as a potential approach to treat various ischemic diseases. However, under many conditions BMC dysfunction has been reported, leading to poor cell engraftment and a failure of tissue revascularization. We have previously shown that skeletal muscle angiogenesis induced by electrical stimulation (ES) is impaired in the SS/Mcwi rats and that this effect is related to a dysregulation of the renin angiotensin system (RAS) that is normalized by the replacement of chromosome 13 derived from the Brown Norway rat (SS-13BN/Mcwi consomic rats). The present study explored bone marrow-derived endothelial cell (BM-EC) function in the SS/Mcwi rat and its impact on skeletal muscle angiogenesis induced by ES. SS/Mcwi rats were randomized to receive BMC from: SS/Mcwi; SS-13BN/Mcwi; SS/Mcwi rats infused with saline or ANG II (3 ng·kg−1·min−1). BMC were injected in the stimulated tibialis anterior muscle of SS/Mcwi rats. Vessel density was evaluated in unstimulated and stimulated muscles after 7 days of ES. BMC isolated from SS/Mcwi or SS/Mcwi rats infused with saline failed to restore angiogenesis induced by ES. However, BMC isolated from SS-13BN/Mcwi and SS/Mcwi rats infused with ANG II effectively restored the angiogenesis response in the SS/Mcwi recipient. Furthermore, ANG II infusion increased the capacity of BM-EC to induce endothelial cell tube formation in vitro and slightly increased VEGF protein expression. This study suggests that dysregulation of the RAS in the SS/Mcwi rat contributes to impaired BM-EC function and could impact the angiogenic therapeutic potential of BMC.

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Therapeutic Perspectives of Angiotensin-(1-7) in the Treatment of Cardiovascular Disease

The Open Pharmacology Journal ◽

10.2174/1874143600903010021 ◽

2009 ◽

Vol 3 (1) ◽

pp. 17-20 ◽

Cited By ~ 3

Author(s):

Christian Höcht ◽

Marcos Mayer ◽

Carlos A. Taira

Keyword(s):

Cardiovascular Disease ◽

Renin Angiotensin System ◽

Therapeutic Strategies ◽

Biologically Active ◽

Ang Ii ◽

Active Components ◽

Aldosterone Antagonists ◽

Angiotensin System ◽

Renin Angiotensin ◽

Beneficial Effects

In the last decade, new biologically active components of the renin-angiotensin system were found. Angiotensin-(1-7) (Ang-(1-7)), a metabolite of angiotensin I and angiotensin II (Ang II), is considered the most pleiotropic component of the renin-angiotensin system, acting as a counterregulatory mediator of Ang II. Ang-(1-7) exerts beneficial effects on the cardiovascular system, including reduction of blood pressure, myocardial antihypertrofic and antifibrotic actions, and reversal of renal dysfunction, among others. Recent discovery of enzymatic pathways involved in Ang-(1-7) synthesis, such as the angiotensin-converting enzyme-2 (ACE2) and the existence of a specific receptor to this heptapeptide, the Mas receptor, have increased interest in the design of therapeutic strategies aimed at increasing the biological actions of Ang-(1-7). ACE inhibitors, AT receptor blockers and aldosterone antagonists enhance Ang-(1-7) levels by different mechanisms. Actually, non-peptidic Ang-(1-7) agonists and ACE2 activators are under development and could have a role in the treatment of cardiovascular diseases. The aim of the present review is to describe the biochemical and physiological actions of Ang-(1-7), the therapeutic strategies designed to enhance Ang-(1-7) activity foccusing in their possible role and limitations in the treatment of cardiovascular disease.

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Renin Angiotensin System in Cognitive Function and Dementia

Asian Journal of Neuroscience ◽

10.1155/2013/102602 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 19

Author(s):

Vijaya Lakshmi Bodiga ◽

Sreedhar Bodiga

Keyword(s):

Cognitive Function ◽

Renin Angiotensin System ◽

Organ Injury ◽

Ang Ii ◽

Microvascular Damage ◽

Angiotensin System ◽

Cerebrovascular Pathology ◽

Beneficial Effects ◽

Mas Receptor ◽

End Stage

Angiotensin II represents a key molecule in hypertension and cerebrovascular pathology. By promoting inflammation and oxidative stress, enhanced Ang II levels accelerate the onset and progression of cell senescence. Sustained activation of RAS promotes end-stage organ injury associated with aging and results in cognitive impairment and dementia. The discovery of the angiotensin-converting enzyme ACE2-angiotensin (1–7)-Mas receptor axis that exerts vasodilator, antiproliferative, and antifibrotic actions opposed to those of the ACE-Ang II-AT1 receptor axis has led to the hypothesis that a decrease in the expression or activity of angiotensin (1–7) renders the systems more susceptible to the pathological actions of Ang II. Given the successful demonstration of beneficial effects of increased expression of ACE2/formation of Ang1–7/Mas receptor binding and modulation of Mas expression in animal models in containing cerebrovascular pathology in hypertensive conditions and aging, one could reasonably hope for analogous effects regarding the prevention of cognitive decline by protecting against hypertension and cerebral microvascular damage. Upregulation of ACE2 and increased balance of Ang 1–7/Ang II, along with positive modulation of Ang II signaling through AT2 receptors and Ang 1–7 signaling through Mas receptors, may be an appropriate strategy for improving cognitive function and treating dementia.

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Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00855.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. H1965-H1975 ◽

Cited By ~ 11

Author(s):

Viktor Pastukh ◽

Songwei Wu ◽

Craig Ricci ◽

Mahmood Mozaffari ◽

Stephen Schaffer

Keyword(s):

Oxidative Stress ◽

Calcium Transport ◽

Renin Angiotensin System ◽

Myocardial Cell ◽

Contractile Dysfunction ◽

Ang Ii ◽

Angiotensin System ◽

Beneficial Effects ◽

Hypoxia Exposure

Myocardial cell death is an important contributor to the development of diabetic cardiomyopathy. It has been proposed that diabetes-mediated upregulation of the renin-angiotensin system leads to oxidative stress, the trigger for cardiomyocyte death and contractile dysfunction. However, the adverse effect of ANG II on the diabetic heart may extend beyond the development of the cardiomyopathy. ANG II also alters specific modulators of ischemic injury, such as PKC and calcium transport. Therefore, the present study examined the effect of ANG II on hyperglycemic preconditioning, a glucose-mediated condition associated with the elevation of PKC activity and alterations in calcium transport that render the cell resistant to hypoxia. Exposure of the glucose-treated cell to ANG II during the prehypoxic period blocked glucose-mediated cardioprotection. The reversal of hyperglycemic preconditioning was associated with enhanced accumulation of Ca2+ during hypoxia, an effect prevented by inhibition of the Na+/ H+ exchanger and the T-type Ca2+ channel. The inhibitors of hypoxia-mediated Ca2+ accumulation also blocked the reversal of hyperglycemic preconditioning by ANG II. Thus ANG II and glucose treatment exert opposite actions on the Na+/ H+ exchanger and the T-type Ca2+ channel. Because those transporters are involved in hypoxia-mediated apoptosis, they are logical candidates for the beneficial effects of high glucose and the adverse effects of ANG II on the hypoxic cardiomyocyte.

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Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

AJP Renal Physiology ◽

10.1152/ajprenal.00655.2013 ◽

2014 ◽

Vol 306 (8) ◽

pp. F812-F821 ◽

Cited By ~ 62

Author(s):

Jun Mori ◽

Vaibhav B. Patel ◽

Tharmarajan Ramprasath ◽

Osama Abo Alrob ◽

Jessica DesAulniers ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Osmotic Pumps ◽

Characteristic Features ◽

Transcription 3

The renin-angiotensin system, especially angiotensin II (ANG II), plays a key role in the development and progression of diabetic nephropathy. ANG 1–7 has counteracting effects on ANG II and is known to exert beneficial effects on diabetic nephropathy. We studied the mechanism of ANG 1–7-induced beneficial effects on diabetic nephropathy in db/db mice. We administered ANG 1–7 (0.5 mg·kg−1·day−1) or saline to 5-mo-old db/db mice for 28 days via implanted micro-osmotic pumps. ANG 1–7 treatment reduced kidney weight and ameliorated mesangial expansion and increased urinary albumin excretion, characteristic features of diabetic nephropathy, in db/db mice. ANG 1–7 decreased renal fibrosis in db/db mice, which correlated with dephosphorylation of the signal transducer and activator of transcription 3 (STAT3) pathway. ANG 1–7 treatment also suppressed the production of reactive oxygen species via attenuation of NADPH oxidase activity and reduced inflammation in perirenal adipose tissue. Furthermore, ANG 1–7 treatment decreased lipid accumulation in db/db kidneys, accompanied by increased expressions of renal adipose triglyceride lipase (ATGL). Alterations in ATGL expression correlated with increased SIRT1 expression and deacetylation of FOXO1. The upregulation of angiotensin-converting enzyme 2 levels in diabetic nephropathy was normalized by ANG 1–7. ANG 1–7 treatment exerts renoprotective effects on diabetic nephropathy, associated with reduction of oxidative stress, inflammation, fibrosis, and lipotoxicity. ANG 1–7 can represent a promising therapy for diabetic nephropathy.

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Alamandine acts via MrgD to induce AMPK/NO activation against ANG II hypertrophy in cardiomyocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00153.2017 ◽

2018 ◽

Vol 314 (6) ◽

pp. C702-C711 ◽

Cited By ~ 22

Author(s):

Itamar Couto Guedes de Jesus ◽

Sérgio Scalzo ◽

Fabiana Alves ◽

Kariny Marques ◽

Cibele Rocha-Resende ◽

...

Keyword(s):

Therapeutic Potential ◽

Renin Angiotensin System ◽

Neonatal Rat ◽

No Production ◽

Ang Ii ◽

New Members ◽

Rat Cardiomyocytes ◽

Angiotensin System ◽

Biologically Relevant ◽

No Signaling

The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. New members of this system have been characterized and shown to have biologically relevant actions. Alamandine and its receptor MrgD are recently identified components of RAS. In the cardiovascular system, alamandine actions included vasodilation, antihypertensive, and antifibrosis effects. Currently, the actions of alamandine on cardiomyocytes are unknown. Here our goal was twofold: 1) to unravel the signaling molecules activated by the alamandine/MrgD axis in cardiomyocytes; and 2) to evaluate the ability of this axis to prevent angiotensin II (ANG II)-induced hypertrophy. In cardiomyocytes from C57BL/6 mice, alamandine treatment induced an increase in nitric oxide (NO) production, which was blocked by d-Pro7-ANG-(1–7), a MrgD antagonist. This NO rise correlated with increased phosphorylation of AMPK. Alamandine-induced NO production was preserved in Mas−/− myocytes and lost in MrgD−/− cells. Binding of fluorescent-labeled alamandine was observed in wild-type cells, but it was dramatically reduced in MrgD−/− myocytes. We also assessed the consequences of prolonged alamandine exposure to cultured neonatal rat cardiomyocytes (NRCMs) treated with ANG II. Treatment of NRCMs with alamandine prevented ANG II-induced hypertrophy. Moreover, the antihypertrophic actions of alamandine were mediated via MrgD and NO, since they could be prevented by d-Pro7-ANG-(1–7) or inhibitors of NO synthase or AMPK. β-Alanine, a MrgD agonist, recapitulated alamandine’s cardioprotective effects in cardiomyocytes. Our data show that alamandine via MrgD induces AMPK/NO signaling to counterregulate ANG II-induced hypertrophy. These findings highlight the therapeutic potential of the alamandine/MrgD axis in the heart.

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20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

Biomedicines ◽

10.3390/biomedicines9050492 ◽

2021 ◽

Vol 9 (5) ◽

pp. 492

Author(s):

Laurence Dinan ◽

Waly Dioh ◽

Stanislas Veillet ◽

Rene Lafont

Keyword(s):

Respiratory Diseases ◽

Therapeutic Potential ◽

Early Stage ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Beneficial Effects ◽

Invertebrate Predators ◽

Polyhydroxylated Steroid

There is growing interest in the pharmaceutical and medical applications of 20-hydroxyecdysone (20E), a polyhydroxylated steroid which naturally occurs in low but very significant amounts in invertebrates, where it has hormonal roles, and in certain plant species, where it is believed to contribute to the deterrence of invertebrate predators. Studies in vivo and in vitro have revealed beneficial effects in mammals: anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, hepatoprotective, etc. The possible mode of action in mammals has been determined recently, with the main mechanism involving the activation of the Mas1 receptor, a key component of the renin–angiotensin system, which would explain many of the pleiotropic effects observed in the different animal models. Processes have been developed to produce large amounts of pharmaceutical grade 20E, and regulatory preclinical studies have assessed its lack of toxicity. The effects of 20E have been evaluated in early stage clinical trials in healthy volunteers and in patients for the treatment of neuromuscular, cardio-metabolic or respiratory diseases. The prospects and limitations of developing 20E as a drug are discussed, including the requirement for a better evaluation of its safety and pharmacological profile and for developing a production process compliant with pharmaceutical standards.

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ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

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