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The aim of this study is to review the role of renin-angiotensin in skin regeneration and wound healing with a focus on molecular mechanisms. Angiotensin receptor type 1 (AT1R) are abundant in the wounded area, and thus, lead to the activation of ERK, STAT1, and STAT3 which can lead to epidermal self-renewal. The expression of Renin Angiotensin System (RAS) components was significantly lower in wounds caused by burning, rather than intact skin, noting that RAS is involved in the re-epithelialization of skin. ERK, STAT and STAT3 are the targets of Ang II, indicating that RAS active components are involved in fibroblast, stem cells and keratinocyte migration. The effect of inhibiting the RAS on wound healing is context-dependent. On one hand, it is suggested that inhibiting RAS during this phase may slow down wound healing speed. On the other hand, studies have shown that RAS inhibition in this phase can lead to α-SMA activation, ultimately accelerating the wound healing process. Most of the investigations indicate that the inhibition of RAS with Angiotensin Receptor Blockers (ARBs) and Angiotensin Converting Enzyme (ACE) plays a significant role in tissue remodeling in the last phase of wound healing. It has been shown that the inhibition of RAS can inhibit scar formation and fibrosis through the downregulation of inflammatory and fibrogenic agents, such as TGF-β, SMAD2/3, and TAK1, PDGF-BB, and HSP47. To sum up, that local administration of RAS regulators might lead to less scar formation and inflammation in the last phase of wound closure. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. Methods: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. Results: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. Conclusions: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting. [ABSTRACT FROM AUTHOR]

In this review, we will cover (i) the proteolytic cascade of the RAAS, (ii) its regulation by multiple feedback-controlled parameters, and (iii) the major effects of the RAAS. For the effects of the RAAS, we focus on the role of the RAAS in the regulation of volume homeostasis and vascular tone, as major determinants of arterial blood pressure. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease. [ABSTRACT FROM AUTHOR]

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. DESIGN: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. SETTING: Forty-three hospitals across the United States. PATIENTS: Biorepository samples of 103 patients. INTERVENTIONS: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. MEASUREMENTS AND MAIN RESULTS: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HRQ2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HRQ4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. CONCLUSIONS: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death. [ABSTRACT FROM AUTHOR]

Obesity is the most common health issue in women of reproductive age, which profoundly affects maternal-fetal health. Despite progress in understanding key inflammatory and metabolic changes, the pathogenesis of the cardiovascular phenotype of obese pregnant women remains to be fully understood. This study aimed at: (i) evaluating the changes of the renin-angiotensin system (RAS) throughout pregnancy in obese vs normal weight (control) women, and (ii) evaluating the presence of any associations between maternal hemodynamic status and RAS changes. Thirty-eight normal weight and nineteen obese pregnant women were included. Clinical assessment, blood samples and maternal hemodynamic evaluation were performed at 12, 20, 30, and 36 weeks, while ultrasound assessment was scheduled at 20, 30, and 36 weeks of gestation. Measurements of sFlt-1, PlGF, Angiotensinogen, Renin, AngII, Ang1-7, ACE and ACE2 were performed by ELISA. Our data show that normotensive obese women had lower placental blood supply, as assessed by UV-Q and UV-Q/EFW, as compared to controls, and significantly higher levels of AngII and AngII/Ang1-7 ratio, which were inversely related to placental blood supply. Our study shows for the first time that normotensive obese women exhibited a significant progressive increase of AngII and AngII/Ang1-7 throughout pregnancy, which were inversely related to placental blood supply as assessed by UV-Q and UV-Q/EFW. Our data shed light on the early changes in pregnant obese women and suggest that RAS dysregulation is a prerequisite rather than a consequence of hypertensive disorders of pregnancy and other maternal neonatal complications. • Angiotensin II significantly increased in normotensive obese pregnant women and this was related to placental blood supply. • Placental blood supply was reduced in normotensive obese pregnant women at 30 weeks of gestation. • Our data suggest that RAS dysregulation may be a prerequisite of hypertensive disorders of pregnancy in obesity. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the brain renin angiotensin system (RAS) plays a pivotal role in the regulation of cognition and behavior as well as in the neuropathology of neurological and mental disorders. The angiotensin II type 1 receptor (AT1R) mediates most functional and neuropathology-relevant actions associated with the central RAS. However, an overarching comprehension to guide translation and utilize the therapeutic potential of the central RAS in humans is currently lacking. We conducted a comprehensive characterization of the RAS using an innovative combination of transcriptomic gene expression mapping, image-based behavioral decoding, and pre-registered randomized controlled discovery-replication pharmacological resting-state functional magnetic resonance imaging (fMRI) trials (N = 132) with a selective AT1R antagonist. The AT1R exhibited a particular dense expression in a subcortical network encompassing the thalamus, striatum, and amygdalo-hippocampal formation. Behavioral decoding of the AT1R gene expression brain map showed an association with memory, stress, reward, and motivational processes. Transient pharmacological blockade of the AT1R further decreased neural activity in subcortical systems characterized by a high AT1R expression, while increasing functional connectivity in the cortico-basal ganglia-thalamo-cortical circuitry. Effects of AT1R blockade on the network level were specifically associated with the transcriptomic signatures of the dopaminergic, opioid, acetylcholine, and corticotropin-releasing hormone signaling systems. The robustness of the results was supported in an independent pharmacological fMRI trial. These findings present a biologically informed comprehensive characterization of the central AT1R pathways and their functional relevance on the neural and behavioral level in humans. [ABSTRACT FROM AUTHOR]

BackgroundChronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators.ObjectivesTo evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD.AnimalsSix client-owned adult dogs with IRIS Stage 2 and 3 CKD.MethodsProspective study. Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2 D), 24,25-dihydroxyvitamin D (24,25[OH]2 D), RAAS mediators (angiotensin I/II/III/IV/1-5/1-7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement.ResultsAll serum vitamin D metabolite concentrations increased significantly by month 3 (P

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Parkinson's disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.

Hypertension during pregnancy increases the risk of adverse maternal and fetal outcomes, but the mechanisms of pregnancy hypertension are not precisely understood. Elevated plasma renin activity and aldosterone concentrations play an important role in the normal physiologic adaptation to pregnancy. These effectors are reduced in patients with pregnancy hypertension, creating an opportunity to define the features of the renin–angiotensin–aldosterone system (RAAS) that are characteristic of this disorder. In the current study, we used a novel LC-MS/MS-based methodology to develop comprehensive profiles of RAAS peptides and effectors over gestation in a cohort of 74 pregnant women followed prospectively for the development of gestational hypertension and pre-eclampsia (HYP, 27 patients) versus those remaining normotensive (NT, 47 patients). In NT pregnancy, the plasma renin activity surrogate, (PRA-S, calculated from the sum of Angiotensin I + Angiotensin II) and aldosterone concentrations significantly increased from the first to the third trimester, accompanied by a modest increase in the concentrations of angiotensin peptide metabolites. In contrast, in HYP pregnancies, PRA-S and angiotensin peptides were largely unchanged over gestation, and third-trimester aldosterone concentrations were significantly lower compared with those in NT pregnancies. The results indicated that the predominant features of pregnancies that develop HYP are stalled or waning activation of the RAAS in the second half of pregnancy (accompanied by unchanging levels of angiotensin peptides) and the attenuated secretion of aldosterone. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin‐I‐converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti‐inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness. [ABSTRACT FROM AUTHOR]

The role of the renin-angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus "receptor") that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, β-arrestin-based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.

The brain angiotensin II acting via AT1 receptors is a prominent mechanism involved in physiological and behavioral responses during aversive situations. The AT2 receptor has also been implicated in stress responses, but its role was less explored. Despite these pieces of evidence, the brain sites related to control of the changes during aversive threats by the brain renin-angiotensin system (RAS) are poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure related to the cardiovascular responses by stress, and components of the RAS system were identified in this forebrain region. Therefore, we investigated the role of angiotensinergic neurotransmission present within the BNST acting via local AT1 and AT2 receptors in cardiovascular responses evoked by an acute session of restraint stress in rats. For this, rats were subjected to bilateral microinjection of either the angiotensin-converting enzyme inhibitor captopril, the selective AT1 receptor antagonist losartan, or the selective AT2 receptor antagonist PD123319 before they underwent the restraint stress session. We observed that BNST treatment with captopril reduced the decrease in tail skin temperature evoked by restraint stress, without affecting the pressor and tachycardic responses. Local AT2 receptor antagonism within the BNST reduced both the tachycardia and the drop in tail skin temperature during restraint. Bilateral microinjection of losartan into the BNST did not affect the restraint-evoked cardiovascular changes. Taken together, these data indicate an involvement of BNST angiotensinergic neurotransmission acting via local AT2 receptors in cardiovascular responses during stressful situations. [ABSTRACT FROM AUTHOR]

Background: There has been a dramatic rise in the prevalence of obesity around the world, and it is now recognized as a major contributor to health problems. Secondary negative health issues, such as high blood pressure, cardiovascular disease, and type 2 diabetes, are more likely to affect those who are overweight and obese. Body fluid regulation and cardiovascular homeostasis are traditionally attributed to the renin-angiotensin-aldosterone system (RAAS), which is a hormone system. Recent studies have revealed the presence of active RAAS in many different tissues. Adipose tissue is one of these tissues where the RAAS has been found to have functional components. Objective: Assessment of renin angiotensin aldosterone possible role in obesity. Methods: PubMed, Google Scholar, and Science Direct were used to search for the terms angiotensin, obesity, and renin-angiotensin-aldosterone system. Although they only looked at the most recent or comprehensive study from July 2003 to July 2022, the authors also looked at references from relevant literature. Documents produced in languages other than English have been rendered invalid due to lack of translation-related information. Dissertations, oral presentations, unpublished publications, conference abstracts, and other items that did not deal with significant scientific research were all ignored. Conclusion: Experiments suggest that the processes that drive adipose tissue development and metabolism in peripheral organs, as well as the effects of angiotensin on appetite and metabolism, contribute to the increased activity of the reninangiotensin system in obesity. Although renin angiotensin aldosterone system antagonists are typically used to treat high blood pressure and heart failure, there is growing evidence that they may also be useful in managing obesity and other metabolic diseases. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors. [ABSTRACT FROM AUTHOR]

Summary: Obstructive sleep apnea is a chronic, sleep‐related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub‐group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between‐study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury is a process associated with cardiologic interventions, such as percutaneous coronary angioplasty after an acute myocardial infarction. Blood flow restoration causes a quick burst of reactive oxygen species (ROS), which generates multiple organelle damage, leading to the activation of cell death pathways. Therefore, the intervention contributes to a greater necrotic zone, thus increasing the risk of cardiovascular complications. A major cardiovascular ROS source in this setting is the activation of multiple NADPH oxidases, which could result via the occupancy of type 1 angiotensin II receptors (AT1R); hence, the renin angiotensin system (RAS) is associated with the generation of ROS during reperfusion. In addition, ROS can promote the expression of NF-κΒ, a proinflammatory transcription factor. Recent studies have described an intracellular RAS pathway that is associated with increased intramitochondrial ROS through the action of isoform NOX4 of NADPH oxidase, thereby contributing to mitochondrial dysfunction. On the other hand, the angiotensin II/ angiotensin type 2 receptor (Ang II/AT2R) axis exerts its effects by counter-modulating the action of AT1R, by activating endothelial nitric oxide synthase (eNOS) and stimulating cardioprotective pathways such as akt. The aim of this review is to discuss the possible use of AT1R blockers to hamper both the Ang II/AT1R axis and the associated ROS burst. Moreover; we suggest that AT1R antagonist drugs should act synergistically with other cardioprotective agents, such as ascorbic acid, N-acetylcysteine and deferoxamine, leading to an enhanced reduction in the reperfusion injury. This therapy is currently being tested in our laboratory and has shown promising outcomes in experimental studies. [ABSTRACT FROM AUTHOR]

Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in glucose impairs Nrf2-related gene expression in diabetic hearts, while AT1 antagonism would aid in Nrf2-mediated antioxidant production and energy replenishment. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 signaling in the diabetic heart. Animals were gavaged with a glucose bolus (2 g/kg) and groups were dissected at T0, T180, and T360 minutes. Nrf2 mRNA was 32% lower in OLETF rats compared to LETO and remained suppressed in response to glucose. LETO Nrf2 mRNA increased 25% at T360 in response to glucose while no changes were observed in diabetic hearts. GCLC and GCLM mRNA decreased in diabetic hearts 33% and 44% respectively and remained suppressed in response to glucose while ARB treatment increased GCLM transcripts 90% at T180. These data illustrate that during T2DM and in response to glucose, cardiac Nrf2's adaptive response to environmental stressors such as glucose is impaired in diabetic hearts and that ARB treatment may aid Nrf2's impaired dynamic response.

The exact mechanisms involved in acute renal injury (AKI) due to renal ischemia-reperfusion (IR) are not fully understood, although it has been shown that the renin-angiotensin system (RAS) may play an important role in IR-associated AKI. RAS is considered as one of the most important vasoactive systems of endocrine, paracrine and intracrine, which is important in the physiological regulation of cardiovascular function, blood pressure, fluid and electrolytes balance. This system exerts a set of beneficial or adverse vascular and renal effects. The two main arms of RAS include "ACE, angiotensin II, AT1 receptor" (vasoconstrictor arm) and "ACE2, angiotensin 1-7, AT2 receptor and Mas receptor" (vasodilator arm). IR and its outputs have been reported to be sex-dependent. On the other hand, systemic and local RAS function in the regulation of renal hemodynamics can also be affected by gender. In fact, sex and sex hormones affect sensitivity to angiotensin II and angiotensin 1-7. This review article examines the role of RAS receptors of the new vasopressor arm versus the classic vasopressor arm and their function interference, as well as sex differences and it's influence on renal blood flow in renal IR Injury.

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) within the brain is implicated in the control of fluid and electrolyte balance, autonomic functions, blood pressure, and energy expenditure. Mouse models are increasingly used to explore these mechanisms; however, sex and dose dependencies of effects elicited by chronic intracerebroventricular (ICV) angiotensin II (ANG II) infusion have not been carefully established in this species. To examine the interactions among sex, body mass, and ICV ANG II on ingestive behaviors and energy balance, young adult C57BL/6J mice of both sexes were studied in a multiplexed metabolic phenotyping system (Promethion) during chronic infusion of ANG II (0, 5, 20, or 50 ng/h). At these infusion rates, ANG II caused accelerating dose-dependent increases in drinking and total energy expenditure in male mice, but female mice exhibited a complex biphasic response with maximum responses at 5 ng/h. Body mass differences did not account for sex-dependent differences in drinking behavior or total energy expenditure. In contrast, resting metabolic rate was similarly increased by ICV ANG II in a dose-dependent manner in both sexes after correction for body mass. We conclude that chronic ICV ANG II stimulates water intake, resting, and total energy expenditure in male C57BL/6J mice following straightforward accelerating dose-dependent kinetics, but female C57BL/6J mice exhibit complex biphasic responses to ICV ANG II. Furthermore, control of resting metabolic rate by ANG II is dissociable from mechanisms controlling fluid intake and total energy expenditure. Future studies of the sex dependency of ANG II within the brain of mice must be designed to carefully consider the biphasic responses that occur in females. [ABSTRACT FROM AUTHOR]

Obesity is associated with the inappropriate activation of the renin-angiotensin system (RAS), which increases arterial pressure, impairs insulin secretion and decreases peripheral tissue insulin sensitivity. RAS blockade reverses these detriments; however, it is not clear whether the disease state of the organism and treatment duration determine the beneficial effects of RAS inhibition on insulin secretion and insulin sensitivity. Therefore, the objective of this study was to compare the benefits of acute vs chronic angiotensin receptor type 1 (AT1) blockade started after the onset of obesity, hyperglycemia and hypertension on pancreatic function and peripheral insulin resistance. We assessed adipocyte morphology, glucose intolerance, pancreatic redox balance and insulin secretion after 2 and 11 weeks of AT1 blockade in the following groups of rats: (1) untreated Long-Evans Tokushima Otsuka (lean control; n = 10), (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF; n = 12) and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day by oral gavage; n = 12). Regardless of treatment duration, AT1 blockade decreased systolic blood pressure and fasting plasma triglycerides, whereas chronic AT1 blockade decreased fasting plasma glucose, glucose intolerance and the relative abundance of large adipocytes by 22, 36 and 70%, respectively. AT1 blockade, however, did not improve pancreatic oxidative stress or reverse impaired insulin secretion. Collectively, these data show that AT1 blockade after the onset of obesity, hyperglycemia and hypertension improves peripheral tissue insulin sensitivity, but cannot completely reverse the metabolic derangement characterized by impaired insulin secretion once it has been compromised.

The Endoplasmic Reticulum Aminopeptidase 1 and 2 (ERAP1 and ERAP2) and Insulin Regulated Aminopeptidase (IRAP) are three M1 zinc metalloproteases whose role in antigen processing is the refining of peptidome either in the Endoplasmic reticulum (ERAP1 and ERAP2), or in the endosomes (IRAP). However, other novel and distinct functions are emerging. Here, we focus specifically on ERAP2. This gene has a peculiar evolutionary history, being absent in rodents and undergoing in humans to a balanced selection of two haplotypes, one of which not expressing the full length ERAP2. These observations suggest that its role in antigen presentation is not essential. An additional, less investigated role is in the regulation of the Renin Angiotensin System (RAS). ERAP1 and ERAP2 cleave Angiotensin II (Ang II) into Ang III and IV, which counteract the action of Ang II whereas IRAP is itself the receptor for Ang IV. We have recently reported that macrophages, independently from the haplotype, express and release a N-terminus ERAP2 "short" form which directly binds IRAP and the two molecules are co-expressed in the endosomes and on the cell membrane. This new evidence suggests that the maintenance of the ERAP2 gene in humans could be due to its activity in the regulation of the RAS system, possibly as an Ang IV agonist. Its role in the immune-mediated diseases as well as in disorders more specifically related to an imbalance of the RAS system, including hypertension, pre-eclampsia but also viral infections such as COVID-19, is discussed here. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is a key hormonal system. In recent years, the functional analysis of the novel axis of the RAS (ACE2/Ang-(1–7)/Mas receptor) revealed that its activation can become protective against several pathologies, including cardiovascular diseases. Mas knockout mice (Mas-KO) represent an important tool for new investigations. Indeed, extensive biological research has focused on investigating the functional implications of Mas receptor deletion. However, although the Mas receptor was identified in neonatal cardiomyocytes and also in adult ventricular myocytes, only few reports have explored the Ang-(1–7)/Mas signaling directly in cardiomyocytes to date. This study investigated the implication of Mas receptor knockout to the cytokine profile, energy metabolism, and electrical properties of mice-isolated cardiomyocytes. Here, we demonstrated that Mas-KO mice have modulation in some cytokines, such as G-CSF, IL-6, IL-10, and VEGF in the left ventricle. This model also presents increased mitochondrial number in cardiomyocytes and a reduction in the myocyte diameter. Finally, Mas-KO cardiomyocytes have altered action potential modulation after diazoxide challenge. Such electrical finding was different from the data showed for the TGR(A1-7)3292 (TGR) model, which overexpresses Ang-(1–7) in the plasma by 4.5, used by us as a control. Collectively, our findings exemplify the importance of understanding the ACE2/Ang-(1–7)/Mas pathway in cardiomyocytes and heart tissue. The Mas-KO mice model can be considered an important tool for new RAS investigations. • Mas knockout mice (Mas-KO) have modulation in cytokines from the left ventricle. • Mas-KO animals present increased mitochondrial number in cardiomyocytes. • Mas-KO cardiomyocytes have altered action potential modulation. [ABSTRACT FROM AUTHOR]

In this multicenter retrospective study, we studied the impact of the concurrent use of renin-angiotensin system inhibitors (RASi) on the outcomes of 229 metastatic renal cell carcinoma (mRCC) patients treated with immunecheckpoint inhibitors (ICI). The findings suggest that RASi could be repurposed to enhance outcomes with ICI in patients with mRCC, which may have a large global impact given their cost-efficacy. Background: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI. Methods: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR). Results: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034). Conclusions: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients. [ABSTRACT FROM AUTHOR]

Background: The cause of short stature remains often unknown. The renin-angiotensin system contributes to growth regulation. Several groups reported that angiotensinconverting enzyme 2 (ACE2)-knockout mice weighed less than controls. Our casecontrol study aimed to investigate if children with short stature had reduced ACE2 expression as compared to controls, and its significance. Materials and Methods: children aged between 2 and 14 years were consecutively recruited in a University Hospital pediatric tertiary care center. Cases were children with short stature defined as height SD ≤ -2 diagnosed with growth hormone deficiency (GHD) or idiopathic short stature (ISS), before any treatment. Exclusion criteria were: acute diseases, kidney disease, endocrine or autoimmune disorders, precocious puberty, genetic syndromes, SGA history. ACE and ACE2 expression were measured in peripheral blood mononuclear cells, angiotensins were measured by ELISA. Results: Children with short stature displayed significantly lower ACE2 expression, being 0.40 fold induction (0.01-2.27) as compared to controls, and higher ACE/ACE2, with no differences between GHD and ISS. ACE2 expression was significantly and inversely associated with the risk of short stature, OR 0.26 (0.07-0.82), and it had a moderate accuracy to predict it, with an AUC of 0.73 (0.61-0.84). The cutoff of 0.45 fold induction of ACE2 expression was the value best predicting short stature, identifying correctly 70% of the children. Conclusions: Our study confirms the association between the reduction of ACE2 expression and growth retardation. Further studies are needed to determine its diagnostic implications. [ABSTRACT FROM AUTHOR]

BackgroundThe cause of short stature remains often unknown. The renin-angiotensin system contributes to growth regulation. Several groups reported that angiotensin-converting enzyme 2 (ACE2)-knockout mice weighed less than controls. Our case-control study aimed to investigate if children with short stature had reduced ACE2 expression as compared to controls, and its significance.Materials and Methodschildren aged between 2 and 14 years were consecutively recruited in a University Hospital pediatric tertiary care center. Cases were children with short stature defined as height SD ≤ −2 diagnosed with growth hormone deficiency (GHD) or idiopathic short stature (ISS), before any treatment. Exclusion criteria were: acute diseases, kidney disease, endocrine or autoimmune disorders, precocious puberty, genetic syndromes, SGA history. ACE and ACE2 expression were measured in peripheral blood mononuclear cells, angiotensins were measured by ELISA.ResultsChildren with short stature displayed significantly lower ACE2 expression, being 0.40 fold induction (0.01-2.27) as compared to controls, and higher ACE/ACE2, with no differences between GHD and ISS. ACE2 expression was significantly and inversely associated with the risk of short stature, OR 0.26 (0.07-0.82), and it had a moderate accuracy to predict it, with an AUC of 0.73 (0.61-0.84). The cutoff of 0.45 fold induction of ACE2 expression was the value best predicting short stature, identifying correctly 70% of the children.ConclusionsOur study confirms the association between the reduction of ACE2 expression and growth retardation. Further studies are needed to determine its diagnostic implications.

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE. [ABSTRACT FROM AUTHOR]

Background: Activation of brain renin angiotensin system is associated with neurodegenerative disorders like Alzheimer's disease (AD). AD is the most common type of dementia. Angiotensin Receptor Blockers (ARBs) like Telmisartan, Azilsartan, Valsartan and Losartan have shown efficacy against animal models of AD. The efficacy of Irbesartan in AD has not been thoroughly investigated. Aluminium chloride (AlCl3) induces AD like pathology in rats. Aim and Objectives: The present work evaluates the efficacy of Irbesartan against AlCl3induced amyloidogenesis and cognitive impairment. Material and Methods: Wistar albino rats were divided into four groups containing six each. Group I (saline 10 ml/kg p.o.) and Group II (AlCl3100 mg/kg p.o.) served as normal control and toxic control respectively. Both the groups were dosed daily for 42 days. Group III and Group IV received Irbesartan (10 mg/kg) and Telmisartan (10 mg/kg) respectively with AlCl3daily for 42 days. The drugs were given 1 hour before theadministration of AlCl3. Y-maze, elevated plus maze and radial arm maze were used to evaluate memory functions on day 0 and 42. Amyloid β (Aβ) content and enzymatic anti-oxidant status in both plasma and brain homogenate were measured and histological studies of brain tissues were done on day 43. Results: AlCl3(100 mg/kg, p.o.) significantly (p<0.05) reduces the cognitive function, increases the concentration of Aβ and causes oxidative stress. Irbesartan (10 mg/kg, p.o.) and Telmisartan (10 mg/kg, p.o.) significantly (p<0.05) reverses AlCl3induced amyloidogenesis and 3 cognitive impairment. Conclusion: So, Irbesartan may be useful against AD and other forms of dementia. [ABSTRACT FROM AUTHOR]

Angiotensin peptides (ANGs) play a central role in the renin–angiotensin–aldosterone system, rendering them interesting biomarkers associated with hypertension. Precise quantification of circulating ANGs holds the potential to assess the activity of angiotensin-converting enzyme (ACE), a key protease targeted by widely prescribed drugs, namely ACE inhibitors. This ability could pave the way for personalised medicine, offering insights into the prescription of inhibitors targeting either the proteases or the receptors within the system. Despite recent developments in liquid chromatography–mass spectrometry (LC-MS) methods for measuring circulating ANG concentrations, comprehensive stability studies of ANGs in human plasma are absent in the literature, raising concerns about the reliability of measured concentrations and their link to clinical conditions. To address this critical gap, we conducted an exhaustive evaluation of the pre-analytical stability of ANG1–10, ANG1–9, ANG1–8, ANG1–7, and ANG1–5. By employing surfactants to mitigate non-specific adsorption and a dedicated mix of protease inhibitors to limit protease activity, we established an MS-based assay for these five peptides. We used this method to quantify circulating concentrations of ANGs in the plasma of 11 healthy donors and 3 patients under kidney dialysis. Our findings revealed that ANG1–10 and ANG1–8 circulate at concentrations ranging from 1 to 10 pM in healthy subjects and exhibit a high degree of correlation. Notably, ANG1–9, ANG1–7, and ANG1–5 were undetectable in any of the 14 patients, despite a sub-picomolar limit of detection. This strikingly contrasts with the reference concentrations reported in the literature, which typically fall within the picomolar range. In light of these discrepancies, we strongly advocate for rigorous pre-analytical considerations and comprehensive stability studies to ensure reliable results. We emphasise the pivotal role of heightened pre-analytical awareness within the clinical chemistry community, and we hope for continued growth in this critical area. • A comprehensive stability study of angiotensin peptides (ANGs) is provided. • This method allows the detection of sub-picomolar ANGs concentrations. • ANGs are very sensitive to protease activity, resulting in fast metabolism. • We measured ANGs concentrations lower than previously reported in literature. [ABSTRACT FROM AUTHOR]

Objectives: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/β-catenin signalling in CKD. Methods: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX. Key findings: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1β, Wnt1, active β-catenin/total β-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy. Conclusions: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/β-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/β-catenin signalling and its downstream targets. [ABSTRACT FROM AUTHOR]

Few millions of new cancer cases are diagnosed worldwide every year. Due to significant progress in understanding cancer biology and developing new therapies, the mortality rates are decreasing with many of patients that can be completely cured. However, vast majority of them require chemotherapy which comes with high medical costs in terms of adverse events, of which cardiotoxicity is one of the most serious and challenging. Anthracyclines (doxorubicin, epirubicin) are a class of cytotoxic agents used in treatment of breast cancer, sarcomas, or hematological malignancies that are associated with high risk of cardiotoxicity that is observed in even up to 30% of patients and can be diagnosed years after the therapy. The mechanism, in which anthracyclines cause cardiotoxicity are not well known, but it is proposed that dysregulation of renin-angiotensin-aldosterone system (RAAS), one of main humoral regulators of cardiovascular system, may play a significant role. There is increasing evidence that drugs targeting this system can be effective in the prevention and treatment of anthracycline-induced cardiotoxicity what has recently found reflection in the recommendation of some scientific societies. In this review, we comprehensively describe possible mechanisms how anthracyclines affect RAAS and lead to cardiotoxicity. Moreover, we critically review available preclinical and clinical data on use of RAAS inhibitors in the primary and secondary prevention and treatment of cardiac adverse events associated with anthracycline-based chemotherapy. [ABSTRACT FROM AUTHOR]

Despite the progressive improvements in diagnosis and therapy during the first 20 years of this century, the morbidity and mortality of patients with heart failure (HF) remain high, resulting in an enormous health and economic burden. Only a further improvement in understanding the pathophysiological mechanisms related to the development of cardiac injury and dysfunction can allow more innovative and personalized approaches to HF management. The renin–angiotensin system (RAS) has a critical role in cardiovascular physiology by regulating blood pressure and electrolyte balance. The RAS is mainly regulated by both angiotensin converting enzyme (ACE) and type 2 angiotensin converting enzyme (ACE2). However, the balance between the various peptides and peptidases constituting the RAS/ACE pathway remains in great part unraveled in patients with HF. This review summarizes the role of the RAS/ACE axis in cardiac physiology and HF pathophysiology as well as some analytical issues relevant to the clinical and laboratory assessment of inter-relationships between these two systems. There is evidence that RAS peptides represent a dynamic network of peptides, which are altered in different HF states and influenced by medical therapy. However, the mechanisms of signal transduction have not been fully elucidated under physiological and pathophysiological conditions. Further investigations are necessary to explore novel molecular mechanisms related to the RAS, which will provide alternative therapeutic agents. Moreover, monitoring the circulating levels of active RAS peptides in HF patients may enable a personalized approach by facilitating assessment of the pathophysiological status of several cardiovascular diseases and thus better selection of therapies for HF patients. [ABSTRACT FROM AUTHOR]

Background/aim: The relationship between the activation of the renin-angiotensin system and the increase in erythropoiesis has been shown in many studies. In addition, the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARB) has been reported to reduce hemoglobin levels in various patient groups at risk for secondary erythrocytosis/polycythemia. The aim of our study is to investigate whether there is a change in hemoglobin levels after starting ACEIs or ARBs in patients who have not used them before. Materials and methods: Three hundred and fifty-one patients who were started on renin angiotensin aldosterone system (RAAS) blockers were evaluated retrospectively. None of the patients had anemia before starting RAAS blockers. A median of 6 (4–12) months after the start of the drug, complete blood count and kidney function tests were evaluated. Hemoglobin values before and after the start of the drug were compared statistically. Results: A statistically significant decrease in mean Hb value was found after starting ACEIs or ARBs (14.39 ± 1.29 g/dL vs 13.98 ± 1.36 g/dL, p < 0.001). The decrease in control Hb values was higher in the ARB group than in the ACEI group (–0.53 ± 0.06 g/dL vs –0.29 ± 0.06 g/dL, p < 0.001). Conclusion: A significant decrease in mean Hb level was detected in the first year following the first administration of ACEIs or ARBs. [ABSTRACT FROM AUTHOR]

Hypertension (HTN) and chronic kidney disease (CKD) are increasingly recognized in pediatric patients and represent risk factors for cardiovascular morbidity and mortality later in life. In CKD, enhanced tubular sodium reabsorption is a leading cause of HTN due to augmented extracellular fluid volume expansion. The renin-angiotensin-aldosterone system (RAAS) upregulates various tubular sodium cotransporters that are also targets of the hormone fibroblast growth factor 23 (FGF23) and its co-receptor Klotho. FGF23 inhibits the activation of 1,25-dihydroxyvitamin D that is a potent suppressor of renin biosynthesis. Here we review the complex interactions and disturbances of the FGF23–Klotho axis, vitamin D, and the RAAS relevant to blood pressure regulation and discuss the therapeutic strategies aimed at mitigating their pathophysiologic contributions to HTN. [ABSTRACT FROM AUTHOR]