Therapeutic opportunities in targeting the protective arm of the renin-angiotensin system to improve insulin sensitivity: a mechanistic review.

In recent years, the knowledge of the physiological and pathophysiological roles of the renin-angiotensin system (RAS) in glucose metabolism has advanced significantly. It is now well-established that blockade of the angiotensin AT1 receptor (AT1R) improves insulin sensitivity. Activation of the AT2 receptor (AT2R) and the MAS receptor are significant contributors to this beneficial effect. Elevated availability of angiotensin (Ang) II) for interaction with the AT2R and increased Ang-(1-7) formation during AT1R blockade mediate these effects. The ongoing development of selective AT2R agonists, such as compound 21 and the novel Ang III peptidomimetics, has significantly advanced the exploration of the role of AT2R in metabolism and its potential as a therapeutic target. These agents show promise, particularly when RAS inhibition is contraindicated. Additionally, other RAS peptides, including Ang IV, des-Asp-Ang I, Ang-(1-9), and alamandine, hold therapeutic capability for addressing metabolic disturbances linked to type 2 diabetes. The possibility of AT2R heteromerization with either AT1R or MAS receptor offers an exciting area for future research, particularly concerning therapeutic strategies to improve glycemic control. This review focuses on therapeutic opportunities to improve insulin sensitivity, taking advantage of the protective arm of the RAS.

Renin-angiotensin blockade ameliorates the progression of glomerular injury in podocyte-specific Ctcf knockout mice.

AIM: Several studies have shown that the progression of proteinuria and renal tissue injury is associated with activation of the intrarenal renin-angiotensin system (RAS). CCCTC-binding factor (CTCF) is a DNA-binding factor that plays an essential role in the regulation of gene expression. In the present study, we aimed to investigate the phenotypic effects of CTCF deficiency in podocytes. METHODS: Angiotensin II type 1 receptor blockers (ARBs) were administered to the podocyte-specific Ctcf knockout mice, and histological and biochemical analyzes were performed. We also investigated the changes in the expression of podocin in podocyte cell cultures with or without stimulation with angiotensin II from glomeruli isolated using magnetic beads from podocyte-specific Ctcf knockout mice. RESULTS: Mice in which Ctcf was deleted from podocytes developed glomerulopathy and mice developed severe progressive proteinuria, and impaired renal function. Moreover, ARBs suppressed the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Both real-time polymerase chain reaction and western blotting showed that podocin expression was decreased in cell cultures stimulated with angiotensin II. Furthermore, RAS components gene expressions in podocyte cell cultures isolated from podocyte-specific Ctcf knockout mice were significantly increased. CONCLUSION: These results suggest that RAS is involved in the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Elucidation of the pathophysiology of podocyte-specific Ctcf knockout mice may provide new insights into the relationship between podocyte injury and chronic glomerulonephritis.

Involvement of Renin-Angiotensin system (RAS) components in mild traumatic brain injury.

The Renin Angiotensin System (RAS) plays a pathophysiological role in traumatic brain injury (TBI) but the evidence of its involvement in mild TBI (mTBI) is still limited. We aimed at investigating the levels of components from both the classical and counter-regulatory axis of the RAS in a mTBI animal model. Mice with mTBI displayed enhanced ACE/Ang II/AT1R axis ipsilateral- and contralaterally to the trauma in the hippocampus and prefrontal cortex during acute (24 and 72 h) and later (30 days) timepoints. Increase in Ang-(1-7) levels alongside reduction in Mas receptor expression in hippocampus and prefrontal cortex was also observed after injury. Conversely, mTBI-mice presented higher expression of AT2 receptor in the contralateral hippocampus and the ipsilateral prefrontal cortex. Importantly, treatment with telmisartan, an AT1R blocker, and perindopril, an ACE inhibitor, were able to prevent mTBI-associated locomotor activity impairment and anxiety-like behavior, corroborating the involvement of RAS in the pathophysiology of mTBI. We provided original evidence that components of classical and alternative RAS axes undergo alterations in key brain areas following a mTBI in a time and hemisphere dependent manner. Our findings also open new avenues for investigating the therapeutic potential of RAS components in mTBI.

Maternal exposure to airborne particulate matter during pregnancy and lactation induces kidney injury in rat dams and their male offspring: the role of vitamin D in pregnancy and beyond.

BACKGROUND: Little is known about the transgenerational effects of maternal exposure to fine particulate matter (PM2.5) on offspring kidney health. This study investigated the effect of maternal administration of PM2.5 or PM2.5 with vitamin D during pregnancy and lactation on renal injury in rat dams and their offspring. METHODS: Nine pregnant Sprague-Dawley rats received oral administration of normal saline, airborne PM2.5, or PM2.5 with vitamin D from gestational day 11 to postpartum day 21. Kidneys of rat dams (n = 3 for each group) and their male offspring (n = 5 for each group) were taken for analysis on postpartum or postnatal day 21. RESULTS: Maternal PM2.5 exposure increased glomerular damage, tubulointerstitial injury, and cortical macrophage infiltration in both dams and pups; all increases were attenuated by vitamin D administration. In dam kidneys, PM2.5 increased the protein expression of vitamin D receptor (VDR), klotho, and tumor necrosis factor-α; vitamin D lessened these changes. The expressions of renin, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-kappa B (NF-κB) p50 decreased in rat dams exposed to PM2.5. In offspring kidneys, exposure to maternal PM2.5 reduced the expression of VDR, renin, angiotensin-converting enzyme (ACE), Nrf2, and NF-κB p50, but increased cytochrome P450 24A1 expression. Maternal vitamin D administration with PM2.5 enhanced VDR, ACE, and NF-κB p50 activities in pup kidneys. CONCLUSION: PM2.5 exposure during nephrogenesis may exert transgenerational renal impairment, and maternal vitamin D intake could attenuate PM2.5-induced kidney damage in mothers and their offspring.

Qingda Granule Attenuates Hypertension-Induced Cardiac Damage via Regulating Renin-Angiotensin System Pathway.

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS: Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.

Angiotensin-(1-7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1-2 randomized clinical trial.

BACKGROUND: The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host's cells via the angiotensin-converting enzyme 2 (ACE2). METHODS: This investigator-initiated, seamless phase 1-2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1-7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2. RESULTS: Between August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0-21] vs. 14 [0-18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1-2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0-21] vs. 14 [0-18] days; absolute difference -5 days, 95% CI [0-7] p = 0.04). CONCLUSIONS: The main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1-7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups. Trial Registration ClinicalTrials.gov Identifier: NCT04633772-Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.

Aldosterone's impact on kidney health: exploring the benefits of mineralocorticoid receptor antagonists for renal protection.

Aldosterone, a hormone synthesized by the adrenal cortex, plays a crucial role in regulating sodium and potassium levels in the kidneys through interaction with the mineralocorticoid receptor (MR) in the distal tubules and collecting ducts. While aldosterone aids in maintaining fluid balance by promoting sodium reabsorption and potassium secretion, elevated levels can lead to inflammation, oxidative stress, and organ damage. Experimental evidence highlights aldosterone's involvement in renal inflammation, collagen deposition, and fibrosis, often exacerbating the effects of therapies like angiotensin-converting enzyme inhibitors (ACEIs) by increasing proteinuria and vascular damage. Conversely, mineralocorticoid receptor antagonists (MRAs) show promise in mitigating these harmful effects. This review integrates current knowledge on aldosterone and MRAs, emphasizing their roles in renal health from both clinical and experimental perspectives. Additionally, the novel drug finerenone has shown favorable renal and cardiovascular outcomes in patients with diabetes and chronic kidney disease (CKD), warranting exploration of its potential use in other disease populations in future research.

Renin-Angiotensin System Inhibition in Patients With Myocardial Injury Complicating Transcatheter Aortic Valve Replacement.

Background: Periprocedural myocardial injury impacts clinical outcome after transcatheter aortic valve replacement (TAVR). The optimal medical management strategy for TAVR-related periprocedural myocardial injury has not been established. Objectives: The authors aimed to investigate the prognostic association of renin-angiotensin system (RAS) inhibitors in patients with periprocedural myocardial injury after TAVR. Methods: In a prospective TAVR registry, patients were retrospectively stratified according to Valve Academic Research Consortium (VARC)-3 periprocedural myocardial injury and RAS inhibitor prescription after TAVR. The main outcomes of interest were prevalence of myocardial injury and cardiovascular death. Logistic and Cox proportional hazards regression were used to analyze outcomes of interest. Results: Among 2,083 eligible patients undergoing TAVR between August 2007 and June 2023, 283 patients (13.8%) developed VARC-3 periprocedural myocardial injury. RAS inhibitors were prescribed in 197 patients (70%) with periprocedural myocardial injury and in 1,251 patients (71.2%) without injury. Compared with patients without periprocedural myocardial injury, patients with myocardial injury had an increased risk of cardiovascular death at 1 year (HRadjusted: 2.08; 95% CI: 1.39-3.11). The use of RAS inhibitors after TAVR was associated with a reduced risk of cardiovascular death in patients with and without periprocedural myocardial injury (HRadjusted: 0.46; 95% CI: 0.22-0.95, and HRadjusted: 0.44; 95% CI: 0.30-0.65, respectively). Conclusions: One out of 7 patients undergoing TAVR experienced periprocedural myocardial injury. VARC-3 periprocedural myocardial injury was associated with a 2-fold increased risk of cardiovascular death at 1 year after TAVR. The favorable association of RAS inhibitor prescription was consistent in patients with and without periprocedural myocardial injury. (SwissTAVI Registry; NCT01368250).

Herbal medicine Oryeongsan (Wulingsan): Cardio-renal effects via modulation of renin-angiotensin system and atrial natriuretic peptide system.

Background: Oryeongsan (Wulingsan, Goreisan) has long been used for the treatment of impaired body fluid metabolism. However, the action mechanisms have not been clearly defined. Recently, effects of Oryeongsan on the body fluid and Na+ metabolism and the action mechanisms have been shown more clearly. The present review focuses on the recent findings on the effects of Oryeongsan in the cardio-renal system in relation with body fluid metabolism and action mechanisms leading to a decrease in blood pressure in animal models of hypertension. Methods: The new and recent findings were searched by using searching systems including PubMed-NCBI and Google-Scholar. Results: Oryeongsan induced an increase in glomerular filtration rate, and natriuresis and diuresis with a decreased osmolality and resulted in a contraction of the body fluid and Na+ balance. These findings were associated with a suppression of abundance of Na+-H +-exchanger isoform 3 expression and V2 receptor/aquaporin2 water channel signaling pathway in the kidney. Further, treatment with Oryeongsan accentuated atrial natriuretic peptide secretion in the atria from spontaneously hypertensive rats in which the secretion was suppressed. In addition, Oryeongsan ameliorated impaired vasodilation in spontaneously hypertensive rats. Conclusion: The effects of Oryeongsan in the kidney, atria, and vessel were accompanied by a suppression of AT1 receptor and concurrent accentuation of abundance of AT2/Mas receptors expression and modulation of the natriuretic peptide system in these organs from hypertensive rats. The review shows multiple sites of action of Oryeongsan and mechanisms involved in the regulation of volume and pressure homeostasis in the body.

Aortic aneurysm: pathophysiology and therapeutic options.

Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin-angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang-(1-7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang-(1-7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang-(1-7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang-(1-7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention.

Optimizing Subsequent CARdiovascular Medication Reintroduction in the Intensive Care Unit.

Importance: Hospital admission for a critical illness episode creates communication breakpoints and can lead to medication discrepancies during hospital stays. Due to the patient's underlying condition and the care setting, chronic medications such as cardiovascular medication are often held, discontinued, or changed to alternative administration routes. Unfortunately, data on the optimal timing of cardiovascular drug reinitiation among intensive care unit (ICU) survivors are lacking. Objective: The primary objective of this study was to describe the prevalence of chronic cardiovascular medication taken before hospital admission and discontinued at ICU discharge and hospital discharge for critically ill patients. A secondary objective was to assess factors associated with medication discontinuation. Design setting and participants: We conducted a multicentered retrospective cohort study at 2 tertiary academic hospitals in Canada. All adult patients taking cardiovascular medication before ICU admission and surviving to hospital discharge between April 1, 2016, and April 1, 2017, were eligible. Main outcomes and measures: The main outcome of the study was the discontinuation of cardiovascular medication prescribed before ICU admission. The outcome was assessed through participants' chart review. Results: We included 352 patients with a median age of 71.0 years. A total of 155 patients (44.03%) had at least 1 cardiovascular medication discontinued during their stay. Our adjusted model uncovered 3 factors associated with cardiovascular medication discontinuation: male sex (odds ratio [OR] = 0.564, 95% confidence interval [CI] = 0.346-0.919), number of cardiovascular medications taken preadmission (OR = 1.669, 95% CI = 1.003-2.777 for 2 medications and OR = 3.170, 95% CI = 1.325-7.583), and the use of vasopressors (OR = 1.770, 95% CI = 1.045-2.997). Conclusion: Our study uncovered that cardiovascular medication discontinuation for ICU patients is frequent, especially for renin-angiotensin system (RAS) blockers. Data from our study could be used to reinforce site-specific protocols of medication reconciliation and optimization, as well as inform future protocols aimed at RAS blocker reinitiation follow-up.

Importance de cette étude: L'admission à l'hôpital pour un épisode de maladie grave crée des ruptures de communication et peut entraîner des écarts dans la médication pendant le séjour à l'hôpital. Il arrive souvent, selon l'état sous-jacent du patient et l'environnement de soins, que les médicaments destinés à traiter des maladies chroniques, comme les médicaments cardiovasculaires, soient poursuivis, cessés ou administrés par d'autres voies. On manque malheureusement de données sur le moment optimal pour la reprise du traitement cardiovasculaire chez les survivants des unités de soins intensifs (USI). Objectifs: L'objectif principal était de décrire la prévalence de l'arrêt, à la sortie de l'USI et de l'hôpital, des médicaments pris par les patients gravement malades pour traiter les maladies cardiovasculaires chroniques avant leur admission. Un objectif secondaire était d'évaluer les facteurs associés à l'arrêt du traitement. Conception sujets et cadre de l'étude: Nous avons mené une étude de cohorte rétrospective multicentrique dans deux hôpitaux universitaires tertiaires canadiens. Étaient admissibles tous les patients adultes qui prenaient des médicaments cardiovasculaires avant leur admission à l'USI entre le 1er avril 2016 et le 1er avril 2017 et qui avaient survécu jusqu'à leur sortie de l'hôpital. Mesures et principaux critères d'intérêt: Le principal critère d'intérêt était l'arrêt du traitement cardiovasculaire prescrit avant l'admission à l'USI. Ce critère a été établi par l'examen des dossiers des sujets. Résultats: Nous avons inclus 352 patients (âge médian : 71,0 ans) desquels 155 (44 %) avaient vu au moins un de leurs médicaments pour traiter une maladie cardiovasculaire cessé pendant leur séjour. Notre modèle corrigé a révélé trois facteurs associés à l'arrêt du traitement cardiovasculaire : être de sexe masculin (rapport de cotes [RC] : 0,564; IC95 % : 0,346-0,919), le nombre de médicaments cardiovasculaires pris avant l'admission (RC : 1,669; IC95 % : 1,003-2,777 pour deux médicaments, et RC : 3,170; IC95 % : 1,325-7,583) et l'utilisation de vasopresseurs (RC : 1,770; IC95 % : 1,045-2,997). Conclusion: Notre étude a révélé que l'arrêt du traitement contre les maladies cardiovasculaires chroniques, en particulier les inhibiteurs du SRA, est fréquent chez les patients hospitalisés aux soins intensifs. Les données de notre étude pourraient servir à renforcer les protocoles de bilan de médication et d'optimisation propre à chaque site de même que pour éclairer les futurs protocoles visant à assurer le suivi de la réinitiation des inhibiteurs du SRA.

Emerging roles of the renin-angiotensin system in select oral diseases.

OBJECTIVES: The renin-angiotensin system (RAS) plays essential roles in cardiovascular and renal function regulation. Recent studies have shown that the RAS components are widely expressed in oral tissues, but their roles in oral diseases remain underexplored. This review aims to summarize the effects of the RAS in select oral diseases including oral squamous cells carcinoma (OSCC), periodontitis, oral submucous fibrosis (OSF), and ageusia/dysgeusia. SUBJECTS AND METHODS: Data searches were performed using PubMed, Web of Science and Scopus through July 2024. A narrative overview of current literature was undertaken to synthesize the contexts with elaboration and summary. RESULTS: In OSCC, ACE/Ang II/AT1R promotes OSCC by inducing angiogenesis, cell proliferation and invasiveness. Conversely, ACE/Ang II/AT2R and ACE2/Ang (1-7)/MasR inhibit OSCC progressions. In periodontitis, ACE/Ang II/AT1R upregulates inflammatory cytokines and promotes osteoclast differentiation factor RANKL, whereas ACE2/Ang (1-7)/MasR exerts opposite effects by preventing inflammation and alveolar bone loss. In OSF, Ang (1-7) counters the profibrotic and proinflammatory action of Ang II. In dysgeusia, Ang II suppresses salt taste responses and enhances sweet taste sensitivities, while Ang (1-7) exhibits opposite effects. CONCLUSIONS: The RAS cascade plays crucial roles in OSCC, periodontitis, OSF and ageusia/dysgeusia. The imbalanced RAS may aggravate the progression of these diseases.

Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors.

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

Genetic Polymorphisms of Angiotensin-Converting Enzyme 1 (ACE1) and ACE2 Associated With Severe Acute Respiratory Syndrome COVID-19 in the Palestinian Population.

As a key enzyme of the renin-angiotensin system (RAS), angiotensin-converting enzyme 2 (ACE2) is a validated receptor for SARS-CoV-2, linking RAS to COVID-19. Functional ACE1/ACE2 gene polymorphisms likely cause an imbalance in the ACE1/ACE2 ratio, triggering RAS imbalance and may contribute to COVID-19 complications. This study aimed to investigate four single nucleotide polymorphisms (SNPs) of ACE1 and ACE2 genes, three for ACE1 (rs4343, rs4342, rs4341) and one for ACE2 (rs2285666), in patients with COVID-19 among the Palestinian population. A total of 130 blood samples were collected, including 50 negative controls without COVID-19 infection, 50 cases with COVID-19 infection but not hospitalized, and 30 patients with severe COVID-19 infection hospitalized in the intensive care unit. Fragments of the ACE1 and ACE2 genes, including the targeted SNPs, were amplified using multiplex PCR and subsequently genotyped by next-generation sequencing with specific virtual probes. Our results revealed that ACE2 rs2285666 GG genotype carriers were more prevalent in COVID-19 patients compared to the control group (P=0.049), while no statistical differences were observed in the distribution of ACE1 (rs4343, rs4342, rs4341) variants between COVID-19 patients and the control group. GA carriers of ACE2, rs2285666, among cases and ICU groups were at lower risk of getting COVID-19 infection (P=0.002 and P=0.013, respectively), and they were unlikely to develop fatigue (P=0.043), headache (P=0.007), loss of smell (P=0.028), and dyspnea (P=0.005). Age and comorbidities such as hypertension and coronary artery disease (CAD) were independent risk factors for COVID-19 disease. Symptoms of COVID-19 patients such as fatigue, headaches, runny noses, and loss of smell were significantly higher in non-hospitalized cases of COVID-19, while dyspnea was more frequent in the ICU patients. In conclusion, these findings indicate that the ACE2 rs2285666 GG genotype is associated with an increased risk of COVID-19 infection. This association suggests a potential genetic predisposition linked to the ACE2 gene, which may influence the susceptibility and severity of the disease.

Patiromer Facilitates Angiotensin Inhibitor and Mineralocorticoid Antagonist Therapies in Patients With Heart Failure and Hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

Exploring the Th2 Response in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Potential Modulator of the Renin-Angiotensin System (RAS) Pathway in Hypertension Development.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is alarmingly increasing alongside the cases of obesity worldwide. MASLD is an underestimated metabolic abnormality closely linked with a higher risk of developing systemic arterial hypertension (SAH). However, the underlying mechanism of association between MASLD and SAH remains unknown. Inflammation may link these two entities by regulating the renin-angiotensin system (RAS). For this reason, in this study, we evaluated the hepatic expression of a cytokine profile and critical molecules in the RAS pathway in patients with morbid obesity and MASLD, both with SAH. We found a statistically significant correlation between ACE levels and the cytokines IL-4, IL-10, and IL-13 of Th2 response. Furthermore, according to a multiple linear regression analysis, the cytokines IL-4 and IL-13 were the best predictors of ACE levels. Moreover, we observed increased hepatic IL-13 expression in patients with morbid obesity, MASLD, and SAH compared to those without SAH. These results allow us to propose, for the first time, that the Th2 response, through regulating the RAS, could play a critical role in developing SAH in individuals with MASLD and obesity.

Impact of inhibition of the renin-angiotensin system on early cardiac and renal abnormalities in Sprague Dawley rats fed short-term high fructose plus high salt diet.

Introduction: The combination of a high fructose and high salt diet typical of western diet induces high blood pressure, aortic stiffening, left ventricular (LV) diastolic dysfunction and impaired renal function in rodents. Despite an activated renin-angiotensin system (RAS) in rats fed high fructose and high salt, acute inhibition of the RAS pathway does not improve cardiac and vascular parameters. It may well be that longer term treatment is required to permit remodeling and improve cardiovascular function. Thus, we hypothesized that chronic RAS inhibition fructose+high salt-fed rats to restore blood pressure (BP) to levels similar to glucose plus normal salt-fed controls will improve cardiorenal function and histopathology. Methods: Male and female Sprague Dawley rats monitored by hemodynamic telemetry were fed 0.4% NaCl chow during baseline, then changed to chow containing either 20% glucose+0.4% NaCl (G) or 20% fructose+4% NaCl (F) and treated with vehicle, enalapril (Enal, 4 mg/kg/d) or losartan (Los, 8 mg/kg/d) by osmotic minipump for 25-26 days. Results: BP was elevated in the fructose+high salt groups of both sexes (P < 0.05) and restored to control levels by Enal or Los. Pulse wave velocity (PWV) was lower in female F+Los rats and cardiac output higher in female F+Enal rats. GFR was not changed by diet or treatment. Fructose+high salt groups of both sexes displayed higher albuminuria that was decreased by Enal in male rats. Cardiac fibrosis and mesangial hypercellularity were greater in fructose+high salt-fed rats of both sexes and improved with either Los or Enal. Discussion: Thus, inhibition of the RAS improves early changes in cardiac and renal histopathology in both sexes and albuminuria in male rats fed high fructose and high salt diet. Functional improvements in cardiorenal parameters may require longer treatment.

Mas receptor blockade impairs exercise-induced cardiac hypertrophy.

Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120 µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes.