The Role of Angiotensin-Converting Enzyme in Immunity: Shedding Light on Experimental Findings.

Angiotensin-converting enzyme (ACE) is a zinc-dependent dicarboxypeptidase with two catalytic components, which has an important role in regulating blood pressure by converting angiotensin I to angiotensin II. ACE breaks down other peptides besides angiotensin I and has a variety of physiological effects together with renal growth and reproduction in men. ACE also acts on innate and acquired immune systems by affecting macrophage and neutrophil function, and these outcomes are exacerbated due to the overexpression of ACE. Overexpression of ACE in macrophages imposes antitumor and antimicrobial response, and it enhances the ability of neutrophils to produced super peroxide that has a bactericidal effect. ACE is also known to contribute to the expression of Major Histocompatibility Complex (MHC) class I and MHC class II peptides through enzymatic alterations of these peptides. Apprehending the expression of ACE and its effects on myeloid cell (myelogenous cells) activity can be promising in therapeutic interventions, including treatment of infection and malignancy.

Angiotensin-converting enzyme 2: a key enzyme in key organs.

2020 marked the 20th anniversary of the discovery of the angiotensin-converting enzyme 2 (ACE2). This major event that changed the way we see the renin-angiotensin system today could have passed quietly. Instead, the discovery that ACE2 is a major player in the severe acute respiratory syndrome coronavirus 2 pandemic has blown up the literature regarding this enzyme. ACE2 connects the classical arm renin-angiotensin system, consisting mainly of angiotensin II peptide and its AT1 receptor, with a protective arm, consisting mainly of the angiotensin 1-7 peptide and its Mas receptor. In this brief article, we have reviewed the literature to describe how ACE2 is a key protective arm enzyme in the function of many organs, particularly in the context of brain and cardiovascular function, as well as in renal, pulmonary and digestive homeostasis. We also very briefly review and refer to recent literature to present an insight into the role of ACE2 in determining the course of coronavirus diseases 2019.

The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors.

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.

Angiotensin involvement in trauma processing-exploring candidate neurocognitive mechanisms of preventing post-traumatic stress symptoms.

The angiotensin-II antagonist losartan is a promising candidate that has enhanced extinction in a post-traumatic stress disorder (PTSD) animal model and was related to reducing PTSD symptom development in humans. Here, we investigate the neurocognitive mechanisms underlying these results, testing the effect of losartan on data-driven and contextual processing of traumatic material, mechanisms proposed to be relevant for PTSD development. In a double-blind between-subject design, 40 healthy participants were randomised to a single oral dose of losartan (50 mg) or placebo, 1 h before being exposed to distressing films as a trauma analogue while heart rate (HR) was measured. Peritraumatic processing was investigated using blurry picture stimuli from the films, which transformed into clear images. Data-driven processing was measured by the level of blurriness at which contents were recognised. Contextual processing was measured as the amount of context information retrieved when describing the pictures' contents. Negative-matched control images were used to test perceptual processing of peripheral trauma-cues. Post-traumatic stress symptoms were assessed via self-report questionnaires after analogue trauma and an intrusion diary completed over 4 days following the experiment. Compared to placebo, losartan facilitated contextual processing and enhanced detail perception in the negative-match pictures. During the films, the losartan group recorded lower HR and higher HR variability, reflecting lower autonomic stress responses. We discuss potential mechanisms of losartan in preventing PTSD symptomatology, including the role of reduced arousal and increased contextual processing during trauma exposure, as well as increased threat-safety differentiation when encountering peripheral trauma-cues in the aftermaths of traumatic events.

The Birth of Angiotensin: An International Compromise.

Irvine Page in the United States and Eduardo Braun-Menéndez in Argentina led teams of investigators that studied the role of the kidney in blood pressure regulation. Contemporaneously in 1939, each team using different methods discovered and described a new substance now known as angiotensin. At the time of discovery, Page called it "angiotonin" and Braun-Menéndez called it "hipertensina," anglicized to "hypertensin." Over time, the importance of this substance in circulatory control, pathophysiology and pharmacology became indisputable and the need for a single name became obvious. In a remarkable accommodation, Page and Braun-Menéndez agreed to forego any claim to priority and chose a name with elements of both. Following this compromise, Page and Braun-Menéndez went on to become leaders in science in their own countries as well as recognition world-wide while, angiotensin and its derivatives have become standard components in the understanding and treatment of diseases of the heart, kidney and brain.

Nitric oxide pathway presumably does not contribute to antianxiety and memory retrieval effects of losartan.

Nitric oxide (NO) and angiotensin (AT) receptors have demonstrated well-established interactions in various physiological phenomena. AT1 receptors can play a part in stress-induced activation of the hypothalamic-pituitary-adrenal axis; also, angiotensinergic neurotransmission plays a pivotal role in stress-evoked physiological responses. On the basis of the stress-modulating characteristics of NO, AT1, and AT2 receptors, the present study evaluated the roles of NO and AT1 receptors in the attenuation of stress-induced anxiety-like behaviors after administration of losartan, an AT1 antagonist. Male Wistar rats were exposed to the communication stress box, using a novel method to induce physical or emotional stress, and losartan (10 mg/kg), losartan+L-NG-nitroargininemethyl ester (L-NAME), L-NAME (1, 10, and 100 mg/kg), and normal saline-treated groups were compared. Losartan had reduced behavioral changes induced by both types of stressor and enhanced memory retrieval. Anxiety-like behaviors were significantly attenuated by administration of losartan, to a greater extent in the emotional rather than physical stress group. None of the injected dosages of L-NAME reversed the antianxiety and memory retrieval effects of losartan. Our results indicate that losartan probably improves memory retrieval and lessens anxiety-like behaviors through mechanisms other than the NO pathway.

Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure.

BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS. OBJECTIVES: A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF. METHODS: Using prospective cohorts with chronic (n = 59) and acute (n = 42) HF, plasma angiotensin analysis was performed using a unique liquid chromatography-mass spectrometry/mass spectroscopy method quantifying circulating and equilibrium levels. Angiotensin II (Ang II) metabolism was examined in human explanted hearts with dilated cardiomyopathy (n = 25). RESULTS: The dynamic range of the RAS was large, with equilibrium angiotensin levels being 8- to 10-fold higher compared with circulating angiotensin levels. In chronic HF patients receiving ACE inhibition, plasma Ang II was suppressed and plasma Ang-(1-7) was elevated, whereas acute HF and patients receiving angiotensin receptor blocker had higher plasma Ang II with lower Ang-(1-7) levels. Suppressed Ang-(1-7)/Ang II ratio was associated with worsening HF symptoms and longer hospitalization. Recombinant human ACE2 effectively metabolized Ang-(1-10) and Ang II into Ang-(1-9) and Ang-(1-7), respectively. Myocardial Ang II levels in explanted human hearts with dilated cardiomyopathy were elevated despite ACE inhibition with elevated chymase activity, and Ang II was effectively converted to Ang-(1-7) by rhACE2. CONCLUSIONS: Plasma angiotensin peptides represent a dynamic network that is altered in HF and in response to rhACE2. An increased plasma Ang-(1-7) level is linked to ACE inhibitor use, whereas acute HF reduced Ang-(1-7) levels and suppressed the Ang-(1-7)/Ang II ratio. Increased chymase activity elevated Ang II levels in failing human hearts. Use of rhACE2 effectively normalized elevated Ang II while increasing Ang-(1-7) and Ang-(1-9) levels.

Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.

Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

Renin-angiotensin system in vertebrates: phylogenetic view of structure and function.

Renin substrate, biological renin activity, and/or renin-secreting cells in kidneys evolved at an early stage of vertebrate phylogeny. Angiotensin (Ang) I and II molecules have been identified biochemically in representative species of all vertebrate classes, although variation occurs in amino acids at positions 1, 5, and 9 of Ang I. Variations have also evolved in amino acid positions 3 and 4 in some cartilaginous fish. Angiotensin receptors, AT1 and AT2 homologues, have been identified molecularly or characterized pharmacologically in nonmammalian vertebrates. Also, various forms of angiotensins that bypass the traditional renin-angiotensin system (RAS) cascades or those from large peptide substrates, particularly in tissues, are present. Nonetheless, the phylogenetically important functions of RAS are to maintain blood pressure/blood volume homeostasis and ion-fluid balance via the kidney and central mechanisms. Stimulation of cell growth and vascularization, possibly via paracrine action of angiotensins, and the molecular biology of RAS and its receptors have been intensive research foci. This review provides an overview of: (1) the phylogenetic appearance, structure, and biochemistry of the RAS cascade; (2) the properties of angiotensin receptors from comparative viewpoints; and (3) the functions and regulation of the RAS in nonmammalian vertebrates. Discussions focus on the most fundamental functions of the RAS that have been conserved throughout phylogenetic advancement, as well as on their physiological implications and significance. Examining the biological history of RAS will help us analyze the complex RAS systems of mammals. Furthermore, suitable models for answering specific questions are often found in more primitive animals.

Angiotensins and Their Receptors in Cardiac and Vascular Injury.

The renin-angiotensin system is involved in hypertension and, thus, in cardiac and vascular injury. In general, angiotensin II is considered as the main mediator of this system but angiotensin IIderived peptides were also shown to exert effects in such diseases. Moreover, it became obvious that different cell and corresponding tissue types are characterized by their own renin-angiotensin system. This system is composed of various peptidic derivatives of the precursor angiotensinogen. Those angiotensinogen-derived peptides can be processed further by peptidases and can bind corresponding receptors. Various clinical trials were initiated considering inhibition of the renin-angiotensin system at different stages in cardiac injuries. Recently, a phase 3 trial using infused angiotensin II (LJPC-501) as treatment option in catecholamine-resistent hypotension was established (ClinicalTrials.gov identifier NCT02338843) although it might be that an influence of AngII-derived peptides is not considered. In general, more intense research on AngII-derived peptides should result in novel strategies and therapeutic options in treatment of cardiac and vascular injuries since these peptides exert actions by themselves, some may interfere with AngII-mediated effects, and some can bind different receptors as well. Consequently, they may also become new promising therapeutics in clinical settings in the future. This short review introduces all currently known angiotensins at once, their production and role related to cardiac and vascular injury, which immune cells show renin-angiotensin system components, and how immune cells containing such components might be involved in such diseases as well.

The Redox-sensitive Induction of the Local Angiotensin System Promotes Both Premature and Replicative Endothelial Senescence: Preventive Effect of a Standardized Crataegus Extract.

Endothelial senescence, characterized by an irreversible cell cycle arrest, oxidative stress, and downregulation of endothelial nitric oxide synthase (eNOS), has been shown to promote endothelial dysfunction leading to the development of age-related vascular disorders. This study has assessed the possibility that the local angiotensin system promotes endothelial senescence in coronary artery endothelial cells and also the protective effect of the Crataegus extract WS1442, a quantified hawthorn extract. Serial passaging from P1 to P4 (replicative senescence) and treatment of P1 endothelial cells with the eNOS inhibitor L-NAME (premature senescence) promoted acquisition of markers of senescence, enhanced ROS formation, decreased eNOS expression, and upregulation of angiotensin-converting enzyme (ACE) and AT1 receptors. Increased SA-ß-gal activity and the upregulation of ACE and AT1R in senescent cells were prevented by antioxidants, an ACE inhibitor, and by an AT1 receptor blocker. WS1442 prevented SA-ß-gal activity, the downregulation of eNOS, and oxidative stress in P3 cells. These findings indicate that the impairment of eNOS-derived nitric oxide formation favors a pro-oxidant response triggering the local angiotensin system, which, in turn, promotes endothelial senescence. Such a sequence of events can be effectively inhibited by a standardized polyphenol-rich extract mainly by targeting the oxidative stress.

Salt-Sensitive Hypertension: Perspectives on Intrarenal Mechanisms.

Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic links between chronic salt intake and the development of hypertension.

Update on the role of angiotensin in the pathophysiology of coronary atherothrombosis.

BACKGROUND: Coronary atherothrombosis due to atherosclerotic plaque rupture or erosion is frequently associated with acute coronary syndromes (ACS). Significant efforts have been made to elucidate the pathophysiological mechanisms underlying acute coronary events. MATERIALS AND METHODS: This narrative review is based on the material searched for and obtained via PubMed up to August 2014. The search terms we used were as follows: 'angiotensin, acute coronary syndromes, acute myocardial infarction' in combination with 'atherosclerosis, vulnerability, clinical trial, ACE inhibitors, inflammation'. RESULTS: Among several regulatory components, the renin-angiotensin system (RAS) was shown as a key pathway modulating coronary atherosclerotic plaque vulnerability. Indeed, these molecules are involved in all stages of atherogenesis. Classically, the RAS is composed by a series of enzymatic reactions leading to the angiotensin (Ang) II generation and activity. However, the knowledge of RAS has expanded and become more complex. The discovery of novel components and their functions has revealed additional pathways that contribute to or counterbalance the actions of Ang II. In this review, we discussed on recent findings concerning the role of different angiotensin peptides in the pathophysiology of ACS and coronary atherothrombosis, exploring the link between these molecules and atherosclerotic plaque vulnerability. CONCLUSIONS: Treatments selectively targeting angiotensins (including Mas and AT2 agonists, ACE2 recombinant, or Ang-(1-7) and almandine in oral formulations) have been tested in animal studies or in small human subgroups, expanding the perspective in the ACS prevention. These novel strategies, especially in the counter-regulatory axis ACE2/Ang-(1-7)/Mas, might be promising to reduce plaque vulnerability and inflammation.

Angiotensin blockade and progressive loss of kidney function in hemodialysis patients: a randomized controlled trial.

BACKGROUND: Glomerular filtration rate (GFR) declines during long-term dialysis treatment. In peritoneal dialysis, blockade of the renin-angiotensin-aldosterone system reduces GFR decline. Observational studies suggest that similar treatment may preserve kidney function in hemodialysis (HD). STUDY DESIGN: A multicenter, randomized, placebo-controlled, double-blinded trial, with 1-year follow-up. SETTING & PARTICIPANTS: Adult HD patients with urine output >300mL/24h, HD vintage less than 1 year, and cardiac ejection fraction >30%. Patients were included from 6 HD centers. INTERVENTION: Patients were randomly assigned to placebo or the angiotensin II receptor blocker irbesartan, 300mg daily. Target systolic blood pressure (BP) was 140mm Hg. OUTCOMES & MEASUREMENTS: Primary outcomes were change in GFR measured as the mean of creatinine and urea renal clearance together with urine volume. Secondary outcomes were change in albuminuria, renin-angiotensin II-aldosterone hormone plasma levels, and time to anuria. RESULTS: Of 82 patients randomly assigned (41 patients in each group), 56 completed 1 year of treatment. The placebo and irbesartan groups were comparable at baseline in terms of sex balance (26 vs 30 men), mean age (62 vs 61 years), median HD vintage (137 vs 148 days), mean HD time (10 vs 11h/wk), median urine volume (1.19 vs 1.26L/d), and mean GFR (4.8 vs 5.7mL/min/1.73m(2)). The target BP level was reached in both groups and BP did not differ significantly between groups over time. Adverse-event rates were similar. GFR declined by a mean of 1.7 (95% CI, 1.2-2.3) and 1.8 (95% CI, 1.1-2.4) mL/min/1.73m(2) per year in the placebo and irbesartan groups, respectively. Mean difference (baseline values minus value at 12 months) between groups was -0.0 (95% CI, -0.8 to 0.8). In each group, 4 patients became anuric. LIMITATIONS: GFR decline rates were lower than expected, reducing the power. CONCLUSIONS: At equal BP levels, we found that irbesartan treatment did not affect the decline in GFR or urine volume significantly during 1 year of treatment in HD patients. Irbesartan treatment was used safely in the studied population.

Reduction of angiotensin A and alamandine vasoactivity in the rabbit model of atherogenesis: differential effects of alamandine and Ang(1-7).

Novel treatments are necessary to reduce the burden of cardiovascular disease (CVD). Alamandine binds to MrgD and is reported to induce vasodilation via stimulation of endothelial nitric oxide synthase (eNOS), but its role in atherogenic blood vessels is yet to be determined. To determine the vasoactive role of alamandine and its precursor AngA in diseased aorta, New Zealand White rabbits were fed a diet containing 1% methionine + 0.5% cholesterol + 5% peanut oil for 4 weeks (MC, n = 5) or control (n = 6). In abdominal aorta, alamandine (1 µM) was added 30 min before a dose-response curve to angiotensin II or AngA (1 nM-1 µM), and immunohistochemistry was used to identify MrgD receptors and eNOS. The thoracic aorta, renal, carotid and iliac arteries were mounted in organ baths. Rings were precontracted with phenylephrine, then a bolus dose of alamandine (1 µM) was added 10 min before a dose-response curve to acetylcholine (0.01 µM-10 µM). The MrgD receptor was localized to normal and diseased aorta and colocalized with eNOS. In control but not diseased blood vessels, alamandine enhanced acetylcholine-mediated vasodilation in the thoracic aorta and the iliac artery (P < 0.05) and reduced it in the renal artery (P < 0.05). In control abdominal aorta, AngA evoked less desensitization than AngII (P < 0.05) and alamandine reduced AngA-mediated vasoconstriction (P < 0.05). In MC, AngA constriction was markedly reduced vs. control (P < 0.05). The vasoactivity of alamandine and AngA are reduced in atherogenesis. Its role in the prevention of CVD remains to be validated.

Estudio traslacional de la vía Notch en nefropatía hipertensiva / Translational study of the Notch pathway in hypertensive nephropathy

Introducción: La ruta de señalización de Notch está activada en una gran variedad de patologías renales humanas. Recientemente hemos demostrado que la activación de esta ruta no estaría implicada en la fibrosis renal experimental inducida por angiotensina II o hipertensión. Objetivos: Evaluar si la vía Notch está activada en la fibrosis renal asociada a nefroesclerosis hipertensiva. Para validar la hipótesis se estudiaron varias patologías glomerulares caracterizadas por fibrosis túbulo-intersticial. Métodos: Se utilizaron biopsias renales de pacientes con nefroesclerosis hipertensiva, en comparación con nefropatía diabética y nefropatía membranosa en diferentes etapas de progresión. La expresión génica y proteica se evaluó por hibridación in situ e inmunohistoquímica, respectivamente. Resultados: En nefroesclerosis hipertensiva se observó baja expresión renal de proteínas de la vía Notch, no existiendo asociación entre la fibrosis túbulo-intersticial y los niveles de estas proteínas. Por el contrario, en las patologías glomerulares estudiadas se observó una elevada expresión de los transcritos Jagged-1, HES-1 y TGF-β, y de las proteínas Jagged-1 y Notch-1, localizados principalmente en células túbulo-epiteliales. Los niveles de expresión de los componentes de la vía Notch se relacionaron con el grado de fibrosis túbulo-intersticial, lo que confirma la activación de esta vía en nefropatías progresivas. Conclusiones: Nuestros datos muestran que la vía Notch no está activada en el riñón de pacientes con nefropatía hipertensiva, ampliando los resultados de los modelos experimentales de daño renal asociado a hipertensión a la patología humana. Nuestros estudios aportan nueva información sobre la compleja regulación del sistema Notch en el riñón (AU)

Introduction: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. Objectives: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. Method: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in-situ hybridisation and immunohistochemistry respectively. Results: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-β and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. Conclusions: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney (AU)

Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson's disease.

Renin-angiotensin systems are known to act in many tissues, for example, the blood vessel wall or kidney, where a close interaction between angiotensin and dopamine has been demonstrated. Regulatory interactions between the dopaminergic and renin-angiotensin systems have recently been described in the substantia nigra and striatum. In animal models, dopamine depletion induces compensatory overactivation of the local renin-angiotensin system, which primes microglial responses and neuron vulnerability by activating NADPH-oxidase. Hyperactivation of the local renin-angiotensin system exacerbates the inflammatory microglial response, oxidative stress, and dopaminergic degeneration, all of which are inhibited by angiotensin receptor blockers and inhibitors of angiotensin-converting enzymes. In this review we provide evidence suggesting that the renin-angiotensin system may play an important role in dopamine's mediated neuroinflammation and oxidative stress changes in Parkinson's disease. We suggest that manipulating brain angiotensin may constitute an effective neuroprotective strategy for Parkinson's disease.

Preoperative angiotensin system inhibitor use attenuates heparin-induced hypotension in patients undergoing cardiac surgery.

OBJECTIVE: Both angiotensin system inhibitor (ASI) use and heparin are associated with hypotension. This study attempted to determine whether preoperative ASI therapy affected the hemodynamic response to heparin administered to patients undergoing cardiac surgery. DESIGN: Sixty-two patients undergoing elective cardiac surgery requiring full (300 units/kg) systemic heparinization were studied prospectively. Thirty-three patients were receiving preoperative ASI therapy, whereas 29 patients were not. Anesthetic technique and mechanical ventilation parameters were standardized. Hemodynamics were recorded at 3 time points: baseline (just before the administration of heparin), 1-minute post-heparin administration, and 4-minute post-heparin administration. SETTING: Single university hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 2 groups were similar regarding preoperative demographics and baseline hemodynamics. Baseline mean arterial pressure (MAP) in non-ASI patients was 82.0 mmHg, and it decreased significantly to 76.3 mmHg (1 min; p<0.05) and 70.7 mmHg (4 min; p<0.05) following heparin administration. MAP values in ASI patients were 81.9 mmHg, 81.8 mmHg, and 76.8 mmHg at baseline, 1-minute post-heparin, and 4-minute post-heparin administration, respectively (changes not significant).Within-group analysis revealed that non-ASI patients experienced significant decrease in MAP at 1-minute (-6.6%, p = 0.01) and 4-minute (-13.0%, p = 0.0011) post-heparin administration, whereas ASI patients did not (+1.9%, p = 0.52; -3.8%, p = 0.16, respectively). Between-group analysis revealed that differences in MAP values at 1 minute were significant (p = 0.03), whereas differences at 4 minutes were not significant (p = 0.05). CONCLUSIONS: This prospective clinical study indicated that preoperative ASI therapy until the day before surgery may attenuate heparin-induced hypotension. Definitive mechanistic insight requires further clinical study.

Renin-angiotensin system: upgrade of recent knowledge and perspectives.

UNLABELLED: Although more than 100 years passed from the renin-angiotensin system (RAS) discovery, new knowledge is still ceaselessly accruing in this field. The present review provides brief overview on the history of the RAS investigation, circulating and tissue RAS, and outlines the physiological functions of the RAS major active substance, angiotensin II (ANG II). Circulating ANG II is generated from angiotensin I (ANG I) by carboxypeptidaze angiotensin-converting enzyme (ACE) expressed in the pulmonary endothelial cells. ANG I is formed from angiotensinogen, originating in the liver, by renal peptidase renin secreted by the juxtaglomerular cells. The ANG II effects are mediated mainly via AT1 receptors. Scientific, medical, and pharmacological interests in the RAS relay mainly in its potency to influence the blood pressure and heart hypertrophy. Inhibition of ACE and AT1 receptors has been shown to be very useful in the hypertension management although several unexpected effects of this treatment led to the initiation of new studies. This review also describes other bioactive angiotensins and modifying enzymes identified during the last years, the ways how the RAS activity can be measured and ANG II degraded in the organism. It also indicates the most convenient models for the RAS investigation. Finally, the major mechanisms of the RAS activity regulation are also described. KEYWORDS: angiotensin, angiotensin-converting enzyme, angiotensin-converting enzyme 2, angiotensin AT1 receptors, experimental model.