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Pflugers Archiv : European Journal of... Mar 2023The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin...
The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1-7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE mice. Vehicle-treated ACE mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE mice. Renal Ang(1-7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1-7) concentration in the ACE mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1-7)/Mas axis, which in turn may deploy its reno-protective effects.
Topics: Mice; Animals; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Angiotensin-Converting Enzyme 2; Angiotensin II; Mice, Inbred C57BL; Renin-Angiotensin System; Renal Insufficiency, Chronic; Angiotensin I; Peptide Fragments
PubMed: 36520238
DOI: 10.1007/s00424-022-02779-4 -
Hormone and Metabolic Research =... Apr 2022The aim of this study is to investigate whether Angiotensin (1-7), the physiological antagonist of Angiotensin II (AngII), has antidiabetic activity and the possible...
The aim of this study is to investigate whether Angiotensin (1-7), the physiological antagonist of Angiotensin II (AngII), has antidiabetic activity and the possible mechanism. Male Wistar rats were randomly divided into 3 groups: control group fed the normal diet, DM group fed high-fat diet and injected with STZ, and Angiotensin (1-7) group receiving injection of STZ followed by Angiotensin (1-7) treatment. Serum Ang II, fasting blood glucose, insulin, HOMA-IR, and HOMA-beta were determined in control, diabetes and Angiotensin (1-7) groups. The increased AngII and insulin resistance in diabetes group were accompanied by changes in islet histopathology. However, Angiotensin (1-7) improved the islet function and histopathology in diabetes without affecting the level of AngII. Western blot confirmed that Angiotensin (1-7) decreased the cleaved caspase 3 levels in pancreas of DM. The increased expression of JNK, Bax, and Bcl2 genes under diabetic conditions were partially reversed after Angiotensin (1-7) administration in pancreas. Immunofluorescence analysis showed that p-JNK was markedly increased in islet of DM rats, which was markedly alleviated after Angiotensin (1-7) treatment. Furthermore, Angiotensin (1-7) reversed high glucose(HG) induced mitochondrial apoptosis augments. Finally, Angiotensin (1-7) attenuated the apoptosis of INS-1 cells through reducing JNK activation in diabetes, which was blocked by anisomycin (a potent agonist of JNK). Our findings provide supporting evidence that Angiotensin (1-7) improved the islet beta-cells apoptosis by JNK-mediated mitochondrial dysfunction, which might be a novel target for the treatment and prevention of beta-cells dysfunction in DM.
Topics: Angiotensin I; Animals; Apoptosis; Blood Glucose; Caspase 3; Diabetes Mellitus, Experimental; Insulin; Male; Peptide Fragments; Rats; Rats, Wistar
PubMed: 35413746
DOI: 10.1055/a-1796-9286 -
Journal of Alzheimer's Disease : JAD 2022Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS)... (Review)
Review
Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.
Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Brain; Cytokines; Dementia, Vascular; Humans; Hypertension; Inflammation; Peptide Fragments; Renin-Angiotensin System
PubMed: 34897090
DOI: 10.3233/JAD-215231 -
Pharmacological Research Dec 2021Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of... (Review)
Review
Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Antifibrotic Agents; Humans; Lung; Molecular Targeted Therapy; Peptide Fragments; Proto-Oncogene Mas; Pulmonary Fibrosis; Renin-Angiotensin System; Signal Transduction
PubMed: 34607005
DOI: 10.1016/j.phrs.2021.105924 -
Molecules (Basel, Switzerland) Mar 2022The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2),... (Review)
Review
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 downregulation, 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.
Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Humans; Receptor, Angiotensin, Type 1; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35408447
DOI: 10.3390/molecules27072048 -
Protein and Peptide Letters 2020The current pharmacological strategies for the management of anxiety disorders and depression, serious conditions which are gaining greater prevalence worldwide, depend... (Review)
Review
The current pharmacological strategies for the management of anxiety disorders and depression, serious conditions which are gaining greater prevalence worldwide, depend on only two therapeutic classes of mood-stabilizing drugs: Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Although first line agents with proven efficacy, their clinical success in the management of anxiety disorders and depression is still considered highly complex due to the multifaceted nature of such conditions. Several studies have shown a possible therapeutic target could be found in the form of the Angiotensin-Converting Enzyme [ACE] type 2 (ACE2), Angiotensin [Ang]-(1-7) and Mas receptor pathway of the Renin- Angiotensin System (RAS), which as will be discussed, has been described to exhibit promising therapeutic properties for the management of anxiety disorders and depression. In this article, the literature to describe recent findings related to the role of the RAS in anxiety and depression disorders was briefly revised. The literature used covers a time range from 1988 to 2019 and were acquired from the National Center for Biotechnology Information's (NCBI) PubMed search engine. The results demonstrated in this review are promising and encourage the development of new research for the treatment of anxiety and depression disorders focusing on the RAS. In conclusion, the ACE2/Ang-(1-7)/Mas pathway may exhibit anxiolytic and anti-depressive effects through many possible biochemical mechanisms both centrally and peripherally, and result in highly promising mental health benefits which justifies further investigation into this system as a possible new therapeutic target in the management of neuropsychiatric disorders, including any as of yet undescribed risk-benefit analysis compared to currently-implemented pharmacological strategies.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Depression; Humans; Peptide Fragments; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 31868143
DOI: 10.2174/0929866527666191223143230 -
Journal of Chemical Information and... Aug 2023Angiotensin-(1-7) is an endogenous peptide known for its vasoprotective, antioxidant, and anti-inflammatory effects, making it a promising therapeutic candidate for...
Angiotensin-(1-7) is an endogenous peptide known for its vasoprotective, antioxidant, and anti-inflammatory effects, making it a promising therapeutic candidate for various clinical conditions. However, the peptide exhibits pH-dependent physical instability in aqueous solutions, and a comprehensive atomistic study elucidating this behavior and its implications is currently lacking. Therefore, we performed all-atom molecular dynamics simulations to investigate the early formation of angiotensin-(1-7) oligomeric aggregates under different conditions: acidic and neutral pH-like conditions, physiological and high ionic strength, and high and low peptide concentrations. Our results are as follows: (1) under acidic pH-like conditions, angiotensin-(1-7) showed minimal clustering, (2) under neutral pH-like conditions, the peptides aggregated into a single cluster, consistent with the reported physical instability, and (3) increasing salt concentration under acidic pH-like conditions resulted in aggregation similar to that observed under neutral pH-like conditions. These results suggest that a combination of salt concentration and pH conditions can modulate angiotensin-(1-7) aggregation. Our protocol (molecular dynamics + cluster analysis + amino acid interaction map analysis) is general and could be applied to other peptides to study interpeptide interaction mechanisms.
Topics: Peptide Fragments; Angiotensin I; Amino Acids; Cluster Analysis; Sodium Chloride
PubMed: 37589289
DOI: 10.1021/acs.jcim.3c00478 -
The European Respiratory Journal Jul 2020In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory,...
BACKGROUND
In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood.
METHODS
We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically.
RESULTS
Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL 0.19, 0.10-0.37 pmol·mL; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL 12.9, 9.55-19.9 ng·dL; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL 4.07, 2.82-6.73 pmol·mL; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL 4.53, 1.47-14.3 ng·mL; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL 5.97, 3.1-17.8 nmol·mL; p<0.001). No significant differences were found among the three different aetiological forms of PAH.
CONCLUSIONS
The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Arterial Hypertension
PubMed: 32241831
DOI: 10.1183/13993003.02416-2019 -
Clinical Science (London, England :... Nov 2020Angiotensin (Ang)-(1-7) is an active peptide formed from Ang I or Ang-(1-9) by multiple proteolytic steps involving angiotensin-converting enzyme (ACE) 1 and other... (Review)
Review
Angiotensin (Ang)-(1-7) is an active peptide formed from Ang I or Ang-(1-9) by multiple proteolytic steps involving angiotensin-converting enzyme (ACE) 1 and other peptidases, or by a single cleavage of Ang II catalyzed chiefly by ACE2. The effects of Ang-(1-7) are mediated by the G protein-coupled receptor Mas (or Mas1), encoded by the protooncogene MAS. The reproductive system expresses ACE2 quite abundantly and therefore is able to generate Ang-(1-7) using precursor peptides produced locally or taken from circulation. In several mammalian species, Ang-(1-7) stimulates ovarian follicle growth, oocyte maturation and ovulation. The peptide is found in human endometrium, mostly during the secretory phase of menstrual cycle when the uterus is receptive to embryo implantation. Rat models and human observational studies suggest that Ang-(1-7) is part of the maternal adaptive response to pregnancy and its deficiency is associated with poor circulation in the placental bed. Knockout mice revealed a relevant participation of Mas-mediated stimulus to the maintenance of normal spermatogenesis, even though the animal can still reproduce without it. In addition, the vasorelaxant effect of Ang-(1-7) participates in the physiological mechanism of corpus cavernosum blood influx and penile erection. We conclude that preclinical evidence encourages the pursuit of treatments for female and male reproductive dysfunctions based on Mas agonists, starting with its natural ligand Ang-(1-7).
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Female; Gonads; Humans; Male; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Reproduction
PubMed: 33196086
DOI: 10.1042/CS20200865 -
Journal of Reproductive Immunology Sep 2022Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The... (Observational Study)
Observational Study
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO and IDO1 cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO and IDO1 cells in the villi. TDO cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7) on the fetal side and in the villi.
Topics: Angiotensin I; Angiotensin II; Female; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Kynurenine; Peptide Fragments; Placenta; Pregnancy; RNA, Messenger; Tryptophan; Tryptophan Hydroxylase; Tryptophan Oxygenase
PubMed: 35970080
DOI: 10.1016/j.jri.2022.103692