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Experimental Biology and Medicine... Nov 2016The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of... (Review)
Review
The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders.
Topics: Aldosterone; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cytochrome P-450 CYP11B2; Humans; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System
PubMed: 27439538
DOI: 10.1177/1535370216660211 -
Current Hypertension Reports Feb 2015The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic... (Review)
Review
The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2-Ang-(1-7)-Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase-phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Humans; Neuroprotective Agents; Peptide Fragments; Peptidyl-Dipeptidase A; Signal Transduction; Stroke
PubMed: 25620630
DOI: 10.1007/s11906-014-0512-2 -
Scientific Reports Jul 2019Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation...
Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the 'classical' and 'alternative' RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early (<2 years), intermediate (2-12 years) or late periods after KTx (>12 years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels (P < 0.01) and higher levels of Ang I (P < 0.05) and Ang-(1-7) (P < 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group (P < 0.005) likely as a consequence of increased allograft chymase activity (P < 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of 'alternative RAS' metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.
Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Enzyme Activation; Female; Gene Expression Regulation, Enzymologic; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Models, Biological; Peptide Fragments; Postoperative Complications; Renin; Renin-Angiotensin System
PubMed: 31278281
DOI: 10.1038/s41598-019-46114-x -
British Journal of Pharmacology May 2017Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and... (Review)
Review
Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1-7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013-2016) on the rapidly progressing research on angiotensin 1-7 revealed that MAS1 and two additional receptors can function as 'angiotensin 1-7 receptors', and this deserves further consideration. In this review we have summarized the information on angiotensin 1-7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1-7 make up a sophisticated cross-regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system.
Topics: Angiotensin I; Animals; Humans; Membrane Proteins; Peptide Fragments; Protein Binding; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 28194766
DOI: 10.1111/bph.13742 -
Therapeutic Advances in Cardiovascular... Aug 2015Angiotensin (Ang) (1-7) is the main component of the depressor and protective arm of the renin-angiotensin system. Ang-(1-7) induces vasodilation, natriuresis and... (Review)
Review
Angiotensin (Ang) (1-7) is the main component of the depressor and protective arm of the renin-angiotensin system. Ang-(1-7) induces vasodilation, natriuresis and diuresis, cardioprotection, inhibits angiogenesis and cell growth and opposes the pressor, proliferative, profibrotic, and prothrombotic actions mediated by Ang II. Centrally, Ang-(1-7) induces changes in mean arterial pressure and this effect may be linked with its inhibitory neuromodulatory action on norepinephrine neurotransmission. The present review is focused on the role of Ang-(1-7) as a protective agent in the brain.
Topics: Angiotensin I; Animals; Blood Pressure; Brain; Humans; Norepinephrine; Peptide Fragments; Renin-Angiotensin System
PubMed: 26287021
DOI: 10.1177/1753944715599875 -
Biomedicine & Pharmacotherapy =... Feb 2019Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney... (Review)
Review
Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 1-7)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI. The preclinical and clinical studies have reported beneficial as well as deleterious effects of RAS blockage either by angiotensin receptor blocker or ACE inhibitor in AKI. On the contrary, the depressor arm opposes the conventional RAS, has beneficial effects on the kidney but has been less explored in pathogenesis of AKI. This review focuses on significance of RAS in pathogenesis of AKI and provides better understanding of novel and possible therapeutic approaches to combat AKI.
Topics: Acute Kidney Injury; Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Renin-Angiotensin System; Signal Transduction
PubMed: 30554115
DOI: 10.1016/j.biopha.2018.12.018 -
Circulation Research Apr 2016Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and... (Review)
Review
Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Heart Failure; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Signal Transduction
PubMed: 27081112
DOI: 10.1161/CIRCRESAHA.116.307708 -
Experimental Physiology Nov 2017What is the central question of this study? The central goal of this study was to understand the effects of central angiotensin-(1-7) on basal and osmotically stimulated...
What is the central question of this study? The central goal of this study was to understand the effects of central angiotensin-(1-7) on basal and osmotically stimulated water intake in rats. What is the main finding and its importance? This study demonstrated that central administration of angiotensin-(1-7) did not induce thirst in basal conditions but increased water intake after osmotic stimulation, such as water deprivation and salt loading. These results indicate a new function for this peptide, which, in turn, allows for future research on the mechanisms through which angiotensin-(1-7) influences osmotic thirst. Angiotensin-(1-7) [Ang-(1-7)] is generated by type 2 angiotensin-converting enzyme (ACE2) and binds to the MAS receptor. Although it is well known that Ang-(1-7) functionally antagonizes the effects of the classical renin-angiotensin system in several situations, the role of Ang-(1-7) in hydromineral homeostasis is not clear. The aim of this study was to assess the role of Ang-(1-7) on neuroendocrine responses to hyperosmolality in rats. Male Wistar rats were divided into the following three groups: control; 24 h of water deprivation (WD); and 24 h of salt loading (SL; 1.8% NaCl). Intracerebroventricular (i.c.v.) injections of Ang-(1-7) or vehicle were given to assess water intake and plasma concentration of vasopressin. Additionally, the brains from control and WD groups were collected to evaluate gene expression in the subfornical organ (SFO), paraventricular nucleus (PVN) and supraoptic nucleus (SON). It was found that i.c.v. Ang-(1-7) did not change water and salt intake in control rats; however, Ang-(1-7) increased water intake after WD and SL, with no change in salt intake. Plasma vasopressin was not changed by i.c.v. Ang-(1-7) in control or WD rats. Moreover, WD increased Mas gene expression in the SON and PVN, with no changes in Ace2 mRNA levels. In conclusion, Ang-(1-7) increases thirst after osmotic stimuli, indicating that a previous sensitization to its action is necessary. This finding is consistent with the increased Mas gene expression in the PVN and SON after water deprivation.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Drinking; Injections, Intraventricular; Male; Osmotic Pressure; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Wistar; Receptors, G-Protein-Coupled; Sodium Chloride; Subfornical Organ; Supraoptic Nucleus; Thirst; Up-Regulation; Vasopressins; Water Deprivation
PubMed: 28833692
DOI: 10.1113/EP086417 -
Journal of Cachexia, Sarcopenia and... Oct 2018A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves...
BACKGROUND
A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1-7 reverses muscle weakness in older mice.
METHODS
After periodic measurement of grip strength and running distance in male ACE2KO and wild-type mice until 24 months of age, we infused angiotensin 1-7 or vehicle for 4 weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3-month-old) and middle-aged (15-month-old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle-aged mice, and some genes were further tested using RT-PCR.
RESULTS
Grip strength of ACE2KO mice was reduced at 6 months and was persistently lower than that of wild-type mice (p < 0.01 at 6, 12, 18, and 24-month-old). Running distance of ACE2KO mice was shorter than that of wild-type mice only at 24 months of age [371 ± 26 vs. 479 ± 24 (m), p < 0.01]. Angiotensin 1-7 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8 ± 1.5 and 13.3 ± 3.1 in wild type and ACE2KO mice, respectively). Older, but not middle-aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age-matched wild-type mice. Angiotensin 1-7 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel-running activity or glucose tolerance between ACE2KO and wild-type mice and between mice with vehicle and angiotensin 1-7 infusion. Analysis of TA muscles revealed that p16INK4a, a senescence-associated gene, and central nuclei of myofibers increased in middle-aged, but not younger ACE2KO mice. p16INK4a and central nuclei increased in TA muscles of older wild-type mice, but the differences between ACE2KO and wild-type mice remained significant (p < 0.01). Angiotensin 1-7 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle ACE2 expression of wild-type mice was the lowest at middle age (2.6 times lower than younger age, p < 0.05).
CONCLUSIONS
Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1-7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.
Topics: Age Factors; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Biomarkers; Disease Models, Animal; Gene Expression Profiling; Glucose Tolerance Test; Mice; Mice, Knockout; Muscle Weakness; Muscle, Skeletal; Oxygen Consumption; Peptide Fragments; Peptidyl-Dipeptidase A; Physical Conditioning, Animal; Transcriptome
PubMed: 30207087
DOI: 10.1002/jcsm.12334 -
Clinical Science (London, England :... Jun 2023Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin...
Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin converting enzymes, ACE and ACE2, angiotensins, and the receptors, AT1 receptor (AT1R) and Mas receptor (MasR), in the regulation of colon functions. The present study tested the hypothesis that leaky gut in aging is associated with an imbalance in ACE2/ACE and that the treatment with angiotenisn-(1-7) (Ang-(1-7)) will restore gut barrier integrity and microbiome. Studies were carried out in Young (3-4 months) and old (20-24 months) male mice. Ang-(1-7) was administered by using osmotic pumps. Outcome measures included expressions of ACE, ACE2, AT1R, and MasR, intestinal permeability by using FITC-dextran, and immunohistochemistry of claudin 1 and occludin, and intestinal stem cells (ISCs). ACE2 protein and activity were decreased in Old group while that of ACE were unchanged. Increased intestinal permeability and plasma levels of zonulin-1 in the Old group were normalized by Ang-(1-7). Epithelial disintegrity, reduced number of goblet cells and ISCs in the old group were restored by Ang-(1-7). Expression of claudin 1 and occludin in the aging colon was increased by Ang-(1-7). Infiltration of CD11b+ or F4/80+ inflammatory cells in the old colons were decreased by Ang-(1-7). Gut microbial dysbiosis in aging was evident by decreased richness and altered beta diversity that were reversed by Ang-(1-7) with increased abundance of Lactobacillus or Lachnospiraceae. The present study shows that Ang-(1-7) restores gut barrier integrity and reduces inflammation in the aging colon by restoring the layer of ISCs and by restructuring the gut microbiome.
Topics: Mice; Male; Animals; Gastrointestinal Microbiome; Angiotensin-Converting Enzyme 2; Dysbiosis; Claudin-1; Occludin; Angiotensin I; Peptidyl-Dipeptidase A; Peptide Fragments; Aging; Angiotensin II
PubMed: 37254732
DOI: 10.1042/CS20220904