angiotensin-i and diminazene-aceturate

Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Mice; Models, Theoretical; Oxidopamine; Parkinson Disease; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Rats; Receptors, G-Protein-Coupled; Signal Transduction

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Diminazene; Disease Models, Animal; Fatty Liver; Female; Gene Expression Regulation; Humans; Liver; Macrophage Activation; Macrophages; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Peptide Fragments; Plaque, Atherosclerotic; Taurine; THP-1 Cells

We have previously demonstrated that the phosphorylation of p38 MAPK, through spinal AT

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Disease Models, Animal; Formaldehyde; Humans; Injections, Spinal; Male; Mice; Microglia; Neurons; Nociception; p38 Mitogen-Activated Protein Kinases; Pain; Peptide Fragments; Peptidyl-Dipeptidase A; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Spinal Cord

This work aims to explore the role of diminazene aceturate (DIZE) in the enhancement of angiotensin-converting enzyme-2 (ACE2) to prevent the inflammatory and fibrotic response induced by γ-irradiation through activating the protective axis ACE2/angiotensin (1-7)/Mas receptor (ACE2/Ang(1-7)/Mas).. Male rats were injected i.p. with 15 mg/kg DIZE daily for 7 days pre and post-irradiation, where 7.5 Gy of γ-radiation as a single dose was used.. Gamma radiation induced a significant elevation of renal biochemical parameters: urea, creatinine and blood urea nitrogen (BUN) in serum with a significant disturbance in oxidative stress markers: elevation in malondialdehyde (MDA) associated with a depletion of reduced glutathione (GSH) and superoxide dismutase (SOD). Beside elevation in the level of angiotensin II (AngII) that lead to remarkably increases in the levels of the renal inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) as well as renal fibrogenic markers: transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and hydroxyproline content in the renal tissues. DIZE caused marked expansion in the expression of ACE2 consequently decreased the expression of AngII and increased the expression of Ang(1-7) which through its Mas receptor ameliorates the biochemical and histopathological damage induced by radiation.. DIZE-induced stimulation of ACE2 subdues the renal deleterious consequences induced by γ-radiation via activation of ACE2/Ang(1-7)/Mas axis in rats.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Gamma Rays; Glutathione; Male; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Superoxide Dismutase

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.

Topics: Angiotensin I; Animals; Cell Line; Chagas Cardiomyopathy; Chagas Disease; Diminazene; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred BALB C; Myocarditis; Myocytes, Cardiac; Myositis; Peptide Fragments; Rats; Renin-Angiotensin System; Trypanocidal Agents

Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Brain Chemistry; Cognitive Dysfunction; Cytokines; Diminazene; Infusions, Parenteral; Male; Maze Learning; Mice; Mice, Neurologic Mutants; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; tau Proteins

The basolateral amygdala (BLA) is critical in the control of the sympathetic output during stress. Studies demonstrated the involvement of the renin-angiotensin system components in the BLA. Angiotensin-(1-7) [Ang-(1-7)], acting through Mas receptors, reduces stress effects. Considering that angiotensin-converting enzyme 2 (ACE2) is the principal enzyme for the production of Ang-(1-7), here we evaluate the cardiovascular reactivity to acute stress after administration of the ACE2 activator, diminazene aceturate (DIZE) into the BLA. We also tested whether systemic treatment with DIZE could modify synaptic activity in the BLA and its effect directly on the expression of the N-methyl-d-aspartate receptors (NMDARs) in NG108 neurons in-vitro. Administration of DIZE into the BLA (200 pmol/100 nL) attenuated the tachycardia to stress (ΔHR, bpm: vehicle = 103 ± 17 vs DIZE = 49 ± 7 p = 0.018); this effect was inhibited by Ang-(1-7) antagonist, A-779 (ΔHR, bpm: DIZE = 49 ± 7 vs A-779 + DIZE = 100 ± 15 p = 0.04). Systemic treatment with DIZE attenuated the excitatory synaptic activity in the BLA (Frequency (Hz): vehicle = 2.9 ± 0.4 vs. DIZE =1.8 ± 0.3 p < 0.04). NG108 cells treated with DIZE demonstrated decreased expression of l subunit NMDAR-NR1 (NR1 expression (a.u): control = 0.534 ± 0.0593 vs. DIZE = 0.254 ± 0.0260) of NMDAR and increases of Mas receptors expression. These data demonstrate that DIZE attenuates the tachycardia evoked by acute stress. This effect results from a central action in the BLA involving activation of Mas receptors. The ACE2 activation via DIZE treatment attenuated the frequency of excitatory synaptic activity in the basolateral amygdala and this effect can be related with the decreases of the NMDAR-NR1 receptor expression.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Basolateral Nuclear Complex; Diminazene; Glutamic Acid; Heart Rate; Neurons; Peptide Fragments; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tachycardia

This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1-7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.

Topics: Acute Kidney Injury; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diabetes Mellitus, Experimental; Diminazene; Imidazoles; Ischemia; Kidney; Liver; Male; Myocardium; Oxidative Stress; Peptide Fragments; Peroxidase; Rats, Wistar; Receptor, Angiotensin, Type 2; Sulfonamides; Thiophenes

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Activators; Humans; Hypertension, Pulmonary; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Ventricular Dysfunction, Left

To investigate the role of angiotensin-converting enzyme 2 (ACE2) in hyperoxic lung injury.. Adult mice were exposed to 95% O2 for 72 h to induce hyperoxic lung injury, and simultaneously treated with ACE2 agonist diminazene aceturate (DIZE) or inhibitor MLN-4760. ACE2 expression/activity in lung tissue and angiotensin (Ang)-(1-7)/Ang II in bronchoalveolar lavage fluid (BALF), and the severity of hyperoxic lung injury were evaluated. The levels of inflammatory factors in BALF and lung tissue and the expression levels of phospho-p65, p65 and IkBα were measured. Oxidative parameter and antioxidant enzyme levels in lung tissue were measured to assess oxidative stress. Finally, the expression levels of nuclear factor-erythroid-2-related factor (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were measured using Western blotting.. Hyperoxia treatment significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio, while co-treatment with hyperoxia and DIZE significantly increased lung ACE2 expression/activity and decreased the Ang II/Ang-(1-7) ratio. By contrast, co-treatment with hyperoxia and MLN-4760 significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio. Hyperoxia treatment induced significant lung injury, inflammatory response and oxidative stress, which were attenuated by DIZE but aggravated by MLN-4760. The NF-κB pathways were activated by hyperoxia and MLN-4760 but inhibited by DIZE. The Nrf2 pathway and its downstream proteins NQO1 and HO-1 were activated by DIZE but inhibited by MLN-4760.. Activation of ACE2 can reduce the severity of hyperoxic lung injury by inhibiting inflammatory response and oxidative stress. ACE2 can inhibit the NF-κB pathway and activate the Nrf2/HO-1/NQO1 pathway, which may be involved in the underlying mechanism.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Bronchoalveolar Lavage Fluid; Diminazene; Hyperoxia; Imidazoles; Leucine; Lung Injury; Male; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiovascular Diseases; Diminazene; Enzyme Activators; Female; Heart; Hypertension, Pregnancy-Induced; Kidney; Male; Myocardial Contraction; Peptide Fragments; Peptidyl-Dipeptidase A; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Ventricular Function, Left

Angiotensin Converting Enzyme (ACE) 2 is an important modulator of the Renin Angiotensin System (RAS) and the RAS plays a central role in renovascular hypertension. Very few studies investigated the role of components of the counterregulatory RAS axis (ACE2, Ang-(1-7) and Mas receptor) in renovascular hypertension and the results are controversial.. The aim of this study was to investigate the effects of Diminazene Aceturate (DIZE) administration on renal function and renal inflammation parameters in 2K1C hypertensive rats.. Male Wistar rats were divided into three experimental groups: sham-operated animals, 2K1C+saline and 2K1C+DIZE orally (1 mg/kg/day). At the end of the 30 days of treatment, renal function was analyzed and kidneys from all the groups were collected and processed separately for measurement of N-acetyl-beta-D-glucosaminidase (NAG) and Myeloperoxidase (MPO) activities, cytokines, chemokines and nitric oxide levels.. Oral DIZE administration for 4 weeks in hypertensive rats attenuated renal dysfunction and reduced the levels of MPO and NAG, cytokines and chemokines (IL1β, IL-6, TNF-α and MCP-1) and increased urinary nitrate/nitrite levels in 2K1C hypertensive rats.. Our findings showed that ACE2 activation may effectively improve renal alterations and inflammation induced by renovascular hypertension.

Topics: Acetylglucosaminidase; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cytokines; Diminazene; Enzyme Activators; Hypertension, Renovascular; Inflammation; Kidney; Male; Nitric Oxide; Peptide Fragments; Peptidyl-Dipeptidase A; Peroxidase; Rats, Wistar; Renin-Angiotensin System

This study was aimed to explore the effect of angiotensin converting enzyme 2 (ACE2) agonist diminazene aceturate (DIZE) on acute lung injury (ALI) induced by limb ischemia-reperfusion (LIR) in mice. Male 8-week-old wild-type and hACE2 transgenic ICR mice were randomly divided into 6 groups (6 in each group), including wild-type control (W), wild-type model (WL), wild-type model with DIZE administration (WLD), transgenic control (T), transgenic model (TL), and transgenic model with DIZE administration (TLD) groups. LIR model was established by 4 h reperfusion following 2 h ischemia of bilateral hindlimbs with rubber bands in mice. The WLD and TLD groups were pretreated with DIZE (15 mg/kg, i.p.) for 4 weeks before LIR. At the end of LIR, the mice were sacrificed and lung tissues were sampled. Indexes for evaluating lung injury include organ coefficient and wet/dry weight ratio (W/D), cell count and protein concentration of bronchoalveolar lavage fluid (BALF), as well as morphological change and pathological score were detected. Angiotensin II (Ang II) and Ang (1-7) levels in lung tissue were determined by using ELISA commercial kits. And the protein expressions of angiotensin II type 1 receptor (AT1) and Mas receptor protein in lung tissue were detected by Western blot. The results were as follows: (1) There was obvious lung injury in both the WL and TL groups. The lung injury in the TL group was lighter than that in the WL group. DIZE could attenuate the lung injury in both the two groups. (2) The WL group showed increased Ang II and decreased Ang (1-7) levels, whereas the TL group did not exhibit any changes of these two proteins. DIZE decreased the level of Ang II in both the WL and TL groups, and increased the level of Ang (1-7) in the WL group. (3) In the WL and TL groups, AT1 and Mas receptor protein expressions were up-regulated. DIZE reversed the change of AT1 protein expression, whereas further increased Mas receptor expression in both the two groups. These results suggest that DIZE may improve the renin-angiotensin system homeostasis by regulating ACE2-Ang (1-7)-Mas axis in local lung tissue and play a protective role in LIR-induced ALI in mice.

Topics: Acute Lung Injury; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Hindlimb; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Reperfusion Injury

The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.

Topics: Adiposity; Age Factors; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Disease Models, Animal; Gene Expression; Male; Obesity; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred F344; Renin-Angiotensin System

The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.

Topics: Albuminuria; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Body Weight; Cytochrome P-450 CYP1A1; Diminazene; Enzyme Activators; Gene Expression Regulation; Hypertension, Malignant; Kidney; Mice; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Rats; Rats, Transgenic; Renin; Renin-Angiotensin System; Sodium

The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent.

Topics: Acetic Acid; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Disease Models, Animal; Ethanol; Female; Gastric Mucosa; Male; Mice; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Stomach Ulcer

Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin angiotensin system, which breaks down angiotensin II and forms angiotensin-(1-7). In erectile tissues, it has been documented that angiotensin II contributes to the development of erectile dysfunction (ED), while treatment with angiotensin-(1-7) improves penile erection. However, the expression and function of ACE2 in erectile tissues have never been investigated.. Here, we examined the expression of ACE2 in erectile tissues and its actions against hypercholesterolemia-induced corpus cavernosum (CC) injury.. Hypercholesterolemic apolipoprotein E knockout (ApoE(-/-) ) mice, a well-known model of ED, were treated with diminazene aceturate (DIZE), an ACE2 activator compound, or vehicle for 3 weeks. Reactive oxygen species (ROS), collagen content, and protein expression of ACE2, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) subunits were evaluated in the penis of DIZE-treated and untreated ApoE(-/-) mice. Functional studies were performed in CC strips.. ACE2 expression and its role in modulating nitric oxide (NO)/ROS production and fibrosis within the CC of hypercholesterolemic mice were the main outcome measures.. ACE2 was expressed in smooth muscle and endothelial cells of mouse CC. Interestingly, ACE2 was downregulated in penis of hypercholesterolemic mice with ED, suggesting a protective role of ACE2 on the CC homeostasis. In accordance with that, pharmacological ACE2 activation by DIZE treatment reduced ROS production and NADPH oxidase expression, and elevated nNOS and eNOS expression and NO bioavailability in the penis of ApoE(-/-) mice. Additionally, DIZE decreased collagen content within the CC. These beneficial actions of DIZE on the CC were not accompanied by improvements in atherosclerotic plaque size or serum lipid profile.. ACE2 is expressed in erectile tissue and its reduction is associated with hypercholesterolemia-induced ED. Additionally, treatment with DIZE improved hypercholesterolemia-induced CC injury, suggesting ACE2 as a potential target for treating ED. .

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Apolipoproteins E; Diminazene; Down-Regulation; Erectile Dysfunction; Hypercholesterolemia; Male; Mice; Mice, Knockout; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penile Erection; Penis; Peptide Fragments; Peptidyl-Dipeptidase A; Reactive Oxygen Species

CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings imply that activation of ACE2/Ang-(1-7)/Mas axis is a promising approach for enhancing reparative outcomes of cell-based therapies.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Antigens, CD34; Cell Adhesion; Cell Movement; Cell Proliferation; Diminazene; Humans; Leukocytes, Mononuclear; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Vasoconstrictor Agents; Vasodilator Agents; Wound Healing; Xanthones

Activation of angiotensin-converting enzyme 2 (ACE2), production of angiotensin-(1-7) [Ang-(1-7)] and stimulation of the Ang-(1-7) receptor Mas exert beneficial actions in various peripheral cardiovascular diseases, largely through opposition of the deleterious effects of angiotensin II via its type 1 receptor. Here we considered the possibility that Ang-(1-7) may exert beneficial effects against CNS damage and neurological deficits produced by cerebral ischaemic stroke. We determined the effects of central administration of Ang-(1-7) or pharmacological activation of ACE2 on the cerebral damage and behavioural deficits elicited by endothelin-1 (ET-1)-induced middle cerebral artery occlusion (MCAO), a model of cerebral ischaemia. The results of the present study demonstrated that intracerebroventricular infusion of either Ang-(1-7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced MCAO significantly attenuated the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions of Ang-(1-7) and DIZE were reversed by co-intracerebroventricular administration of the Mas receptor inhibitor, A-779. Neither the Ang-(1-7) nor the DIZE treatments altered the reduction in cerebral blood flow elicited by ET-1. Lastly, intracerebroventricular administration of Ang-(1-7) significantly reduced the increase in inducible nitric oxide synthase mRNA expression within the cerebral infarct that occurs following ET-1-induced MCAO. This is the first demonstration of cerebroprotective properties of the ACE2-Ang-(1-7)-Mas axis during ischaemic stroke, and suggests that the mechanism of the Ang-(1-7) protective action includes blunting of inducible nitric oxide synthase expression.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diminazene; Endothelin-1; Enzyme Activation; Infarction, Middle Cerebral Artery; Male; Nitric Oxide Synthase Type II; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Stroke