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SARS-CoV-2 targets angiotensin-converting enzyme-2 (ACE2), a key peptidase of the renin-angiotensin system (RAS), which regulates the balance of the vasoconstrictor/inflammatory peptide Ang II and the vasodilator/anti-inflammatory peptide Ang-(1-7). Few studies have quantified the circulating elements of the RAS longitudinally in SARS-CoV-2 infection and their association with COVID-19 outcomes. Thus, we evaluated the association of circulating RAS enzymes and peptides with mortality among patients with COVID-19. Blood samples were collected from 111 patients with COVID-19 and new-onset hypoxemia during the delta and omicron waves at 19 hospitals in the United States. Circulating RAS components were quantified via radioimmunoassay or ELISA at 0 (baseline), 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal RAS concentrations with 90-day mortality. Participants were aged 18-90 (means [SD]: 55 [14]) yr and 62% were male. There were 22 (20%) deaths over 90 days of follow-up. ACE2 levels above the sample median (≥4.9 pM; adjusted HR [95% CI]: 0.10 [0.02, 0.43]) and ACE2/ACE ratio (≥6.0 × 10 -3 ; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log 2 -normalized, time-varying predictors from day 0 to day 5 , twofold increments of ACE2 and ACE2/ACE ratio over this period were associated with lower mortality (adjusted HR: 0.79 [0.65, 0.97] and 0.78 [0.63, 0.97], respectively). Circulating Ang II, Ang-(1-7), and ACE levels were not associated with mortality. These results suggest higher circulating ACE2 protein in hospitalized patients with COVID-19 is associated with reduced mortality. NEW & NOTEWORTHY We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.

Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating the effects of these factors. Recent evidence shows patient-specific alterations of RAS peptide homeostasis concentrations with premorbidity and the expression level of angiotensin-converting enzyme 2 (ACE2) during COVID-19. However, conflicting evidence suggests decreases, increases, or no changes in RAS peptides after SARS-CoV-2 infection. A multiscale computational model was developed to quantify the systemic contribution of heterogeneous factors of RAS during COVID-19. Three submodels were connected-an agent-based model for in-host COVID-19 response in the lung tissue, a RAS dynamics model, and a fibrosis dynamics model to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicated cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2. The model explained possible mechanisms for conflicting evidence of patient-group-specific changes in RAS peptides in previously published studies. RAS peptides decreased for all virtual patient groups with aging in both sexes. In contrast, large variations in the magnitude of reduction were observed between male and female virtual patients in the older and middle-aged groups. The patient-specific variations in homeostasis RAS peptide concentrations of SARS-CoV-2-negative patients affected the dynamics of RAS during infection. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: Our aim was to assess sex differences in the efficacy of angiotensin receptor blockers (i.e. losartan and irbesartan) on kidney and cardiovascular outcomes in individuals with type 2 diabetes and diabetic kidney disease., Methods: Data from the Angiotensin II Antagonist Losartan Study (RENAAL) and Irbesartan type II Diabetic Nephropathy Trial (IDNT) were used. The kidney outcome was time to first event of end-stage kidney disease or doubling of serum creatinine. The cardiovascular outcome was time to first event of a composite of stroke, myocardial infarction, cardiovascular death or hospitalisation for heart failure. Sex differences were assessed by a sex × treatment interaction term in Cox proportional hazards models., Results: Included were 1737 male participants and 924 female participants. The beneficial effect of angiotensin receptor blockers on the kidney outcome was similar between male and female participants (HR in male participants 0.72 [95% CI 0.59, 0.86] vs HR in female participants 0.86 [95% CI 0.69, 1.06]; sex × treatment interaction HR 1.19 [95% CI 0.89, 1.59]). For the cardiovascular outcome, angiotensin receptor blockers lowered the risk in male but not in female participants (HR in male participants 0.81 [95% CI 0.69, 0.95] vs HR in female participants 1.11 [95% CI 0.88, 1.40]; sex × treatment interaction HR 1.37 [95% CI 1.03, 1.82])., Conclusions/interpretation: This study in individuals with type 2 diabetes and diabetic kidney disease suggests that the beneficial effects of angiotensin receptor blockers are similar in male and female participants for the kidney outcome but not for the cardiovascular outcome. More attention to sex differences in angiotensin receptor blockers' efficacy and underlying mechanisms of differences in response is needed., Trial Registration: ClinialTrials.gov NCT00308347., Competing Interests: Data availability statement: The data used for this study are available upon reasonable request to the corresponding author. Funding: This study was conducted in the context of the BEAt-DKD project. This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115974. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and JDRF. Any dissemination of results reflects only the authors’ view; the JU is not responsible for any use that may be made of the information this study contains. Funding was also obtained from European Union’s HORIZON Research and Innovation Actions (HORIZON-HLTH-2022-TOOL-11-01 - Tools and technologies for a healthy society) undertaking under grant agreement no. 101095146. The views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. SAEP is supported by a Vidi Fellowship from the Dutch Organisation for Health Research and Development (ZonMW) (09150172010050). HJLH is supported by Vidi grant from the Netherlands Organisation for Scientific Research (917.15.306). Authors’ relationships and activities: DHvR has acted as a consultant and received honoraria from Boehringer Ingelheim and Lilly, Merck, Bayer and AstraZeneca and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca and Merck. CA has received honoraria from Astra Zeneca, Novo Nordisk and Amgen. AAV has acted as a consultant for AnaCardio, Bayer, BMS, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Novartis, Novo Nordisk and Roche Diagnostics. HJLH is a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, DImerix, Eli Lilly, Fresenius, Gilead, Janssen, NovoNordisk, Novartis and Travere Therapeutics. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: STdV and MJP contributed to the analyses, to the interpretation of the data and writing of the manuscript. SCT conducted the analyses. SCT, SAEP, DHvR, CA, AAV, PGMM and PD contributed to the interpretation of the data and writing of the manuscript. HJLH provided the data and contributed to the interpretation of the data and writing of the manuscript. All authors read and approved the manuscript. HJLH is responsible for the integrity of the work as a whole., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Non-steroidal anti-inflammatory drugs (NSAIDs), though designed to target specific molecular pathways, pose significant environmental risks to non-target organisms, particularly marine fish. This study investigated the toxicity mechanisms and adaptive responses to diclofenac (DCF) and meloxicam (MEX) during the early life stages (ELS) of Oryzias melastigma at environmentally relevant concentrations over a 31-day period. Mechanistic investigations of sub-lethal effects were conducted using Enzyme-Linked Immunosorbent Assay (ELISA), RNA sequencing (RNA-Seq) and quantitative PCR (qPCR). The results revealed that cyclooxygenase (COX) inhibition disrupted the renin-angiotensin system, leading to an accumulation of angiotensin II and cardiovascular developmental defects. Additionally, downregulation of the pla2 gene reduced substrates essential for COX enzyme activity, exacerbating the effects. Although NSAIDs are known to affect the digestive system, no significant effects on developmental factors were observed. RNA-Seq and qPCR analyses revealed an adaptive upregulation of key genes, including ace2 and cyp7a1, involved in cardiovascular and metabolic regulation. Furthermore, 16S rRNA sequencing identified shifts in the microbial community, particularly in g_Rubritalea and g_Sphingomonas genera. Both the upregulated genes and the altered microbial taxa likely played a role in mitigating toxic effects and promoting homeostasis. Moreover, molecular docking suggested that MEX exhibited stronger sub-lethal effects than DCF, likely due to its higher binding affinity to COX. These findings provide valuable insights into NSAID toxicity mechanisms in marine fish, highlighting the importance of adaptive responses in countering environmental stress and underscoring the long-term ecological risks of chronic NSAID exposure., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Objective: Type 2 Diabetes Mellitus (T2DM) is a global health concern, with complications such as diabetic nephropathy (DN) affecting 16.6% of patients and contributing to end-stage renal failure. Emerging research suggests that gut microbial communities may influence DN progression, potentially through mechanisms involving the renin-angiotensin system (RAS). This study aimed to evaluate changes in specific microbial genera in individuals with T2DM, both with and without DN, and to explore their associations with renal function markers and RAS activation., Methods: A total of 120 participants were categorized into three groups: healthy controls, T2DM without DN, and T2DM with DN. Microbial abundances of genera including Escherichia, Prevotella, Bifidobacterium, Lactobacillus, Roseburia, Bacteroides, Faecalibacterium, and Akkermansia were quantified using qPCR targeting the bacterial 16 S rRNA gene. Gene expression levels of RAS-associated markers (ACE, AGT1R, AT2R, and Ang II) and inflammation-related genes (TNF-α, TLR4) were analyzed in peripheral blood mononuclear cells via qPCR., Results: The study identified significant alterations in microbial composition. Genera such as Faecalibacterium, Akkermansia, Roseburia (butyrate producers), and Bifidobacterium (a potential probiotic) were markedly reduced in T2DM and DN groups compared to controls. Increased mRNA expression of RAS-related genes, including ACE, AGT1R, and Ang II, was observed in these groups. We also foun correlations between altered microbial genera, RAS gene expression, and clinical markers of renal dysfunction., Conclusion: The findings suggest that specific microbial genera may influence the pathogenesis of DN through RAS activation and inflammatory pathways. These insights highlight potential therapeutic targets for mitigating DN progression in T2DM patients., Competing Interests: Competing interestsThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Tehran University of Medical Sciences 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Treatment of patients with chronic kidney disease (CKD) requires implementation of prevention and management strategies that reduce the risk of kidney failure and CKD-associated cardiovascular risk. Metabolic syndrome is characterised by obesity, high blood pressure, dyslipidaemia and hyperglycaemia, and is common among patients with CKD. Large-scale randomised trials have led to significant advances in the management of CKD with five pharmacotherapies now proven to be nephroprotective and/or cardioprotective in certain types of patients. Renin-angiotensin system inhibitors and sodium-glucose co-transporter 2 inhibitors slow kidney disease progression and reduce heart failure complications for most patients with CKD. In addition, statin-based regimens lower low-density lipoprotein cholesterol and reduce the risk of atherosclerotic disease (with no clinically meaningful effect on kidney outcomes). For patients with type 2 diabetes and albuminuric CKD, the non-steroidal mineralocorticoid receptor antagonist finerenone and the glucagon-like peptide-1 receptor agonist semaglutide also confer cardiorenal benefits, with semaglutide additionally effective at reducing weight. Together, these randomised data strongly suggest that metabolic syndrome mediates some of the cardiorenal risk observed in CKD. Considered separately, the trials help elucidate which components of metabolic syndrome influence the pathophysiology of kidney disease progression and which separately modify risk of atherosclerotic and non-atherosclerotic cardiovascular outcomes. As we predict complementary and different mechanisms of nephroprotection and cardioprotection for these different interventions, it seems logical that they should be deployed together to maximise benefits. Even when combined, however, these therapies are not a cure so further trials remain important to reduce the residual cardiorenal risks associated with CKD., (Copyright © 2025. Published by Elsevier Inc.)

Background: No standardized index exists to assess cardiovascular responsiveness to angiotensin-II. We hypothesized that a standardized index of initial blood pressure response to angiotensin-II treatment would be associated with clinical outcomes., Methods: Using data from the Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we developed an Angiotensin-II Initial MAP Response Index of Treatment Effect (AIMRITE) defined as (MAP at hr1 - MAP at baseline)/study drug dose. We assessed AIMRITE continuously and, based on observed distributions, we additionally categorized patients as "responsive" or "resistant", with responsiveness defined by an AIMRITE ≥ 0.90 mmHg/ng/kg/min. The primary clinical outcome was 28-day mortality. Secondary outcomes included days alive and vasopressor- or ventilator- or renal replacement therapy-free at day-7. Biological outcomes included baseline renin, angiotensin-II, and renin/angiotensin-II ratio, and their change at hr3., Results: Of 158 placebo patients, as expected, 157 (99%) had AIMRITE < 0.90 mmHg/ng/kg/min (median AIMRITE 0.02; IQR - 0.03-0.10). In contrast, 163 patients assigned to angiotensin-II had a median AIMRITE of 1.43 mmHg/ng/kg/min (IQR 0.35-2.83). Of these, 97 (60%) were responsive (median AIMRITE 2.55; IQR 1.66-4.12) and 66 (40%) were resistant (median AIMRITE 0.24; IQR 0.10-0.52). Each 1.0-unit increase in AIMRITE was associated with a 16% lower hazard of death (HR: 0.84 per-mmHg/ng/kg/min [95% CI 0.74-0.95], p = 0.0062). Responsive patients had half the mortality hazard than resistant patients (HR: 0.50 [95% CI 0.32-0.78], p = 0.0026) and placebo patients (HR 0.58 [95% CI 0.40-0.86], p = 0.0064). Resistant patients had a similar mortality hazard to placebo (HR 1.17 [95% CI 0.80-1.72], p = 0.41). Compared to resistant patients, responsive patients had lower baseline renin and renin/angiotensin-II ratio, but a greater decrease in both at hr3. When stratified by baseline renin level, mortality was highest in placebo patients with high renin (69%) and angiotensin-II resistant patients with low renin (61%)., Conclusions: Among patients with catecholamine-refractory vasodilatory shock treated with angiotensin-II, the AIMRITE was associated with mortality at day-28. Responsive angiotensin-II patients had higher survival versus both angiotensin-II resistant patients and those treated with placebo plus standard vasopressors. This index may serve as a prognostic indicator and early identifier of patients most likely to benefit from angiotensin-II., Competing Interests: Declarations. Ethics approval and consent to participate: The trial was conducted in accordance with Good Clinical Practice guidelines, applicable local regulations, and Declaration of Helsinki principles. The respective independent institutional review boards reviewed the protocol, informed-consent form, and all other documents before study initiation. Competing interests: DEL, LWB, KAH, AKK, MO, and MTC declare no competing interests. RB has received consulting fees from both Innoviva and Viatris as well as research grants from Innoviva. DRH, CDA, and TNH are employees of Innoviva Specialty Therapeutics, Inc., of which La Jolla Pharmaceutical Company is an affiliate. LSC declares that he was formerly an employee of LJPC. PMW is a consultant for Wolters Kluwer/UpToDate and previously received consulting fees from Viatris., (© 2025. The Author(s).)

Cardiovascular-kidney-metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental exposures or mechanisms, are used to explore the developmental origins of CKMS. However, no single model can fully replicate all aspects of CKMS or its clinical stages, limiting the advancement of preventive and therapeutic strategies. This review aims to assist researchers by comparing the strengths and limitations of common animal models used in CKMS programming studies and highlighting key considerations for selecting suitable models.

Background: The mediating role of inflammatory biomarkers in the causal relationship between body composition and hypertension remains unclear and requires further investigation., Methods: This study used a combination of retrospective observational analysis and Mendelian randomization approaches. Observational data were derived from 4717 Chinese children and adolescents aged 6 to 18 years who underwent dual-energy X-ray absorptiometry to assess body composition. Mendelian randomization analyses utilized summary statistics from large-scale data sets, including UK Biobank, deCODE2021, International Consortium of Blood Pressure, FinnGen, and other consortia. The inflammatory biomarkers included leptin, insulin, adiponectin, osteocalcin, FGF23 (fibroblast growth factor 23), and PTH (parathyroid hormone)., Results: The observational analysis revealed that increased fat mass positively influenced diastolic blood pressure through osteocalcin, while fat-free mass had an inverse effect. Insulin mediated the association between fat mass and systolic blood pressure, diastolic blood pressure, and hypertension, with additional indirect effects observed for PTH (all P <0.05). The Mendelian randomization analyses demonstrated a causal relationship between childhood body mass index and hypertension mediated by insulin (indirect effect: odds ratio, 0.87 [95% CI, 0.78-0.97]) and adiponectin (odds ratio, 1.13 [95% CI, 1.04-1.23]). Adiponectin mediated the effects of fat-free mass (odds ratio, 0.81 [95% CI, 0.71-0.93]) and fat mass (odds ratio, 1.30 [95% CI, 1.11-1.51]) on hypertension. Leptin, adiponectin, and insulin also mediated the causal effects of body composition on systolic blood pressure, diastolic blood pressure, and hypertension., Conclusions: These findings indicate that body composition influences blood pressure through distinct inflammatory biomarkers. Targeting inflammatory biomarkers may provide tailored strategies for managing body composition and hypertension.

Besides playing a critical role in maintaining cardiovascular homeostasis, the renin-angiotensin-aldosterone system (RAS) has been strongly implicated in (aortic) aneurysm pathogenesis. This study aims to investigate systemic and local levels of angiotensin (Ang) and its metabolites in patients with arterial aneurysms, predominantly abdominal aortic aneurysms, using advanced biochemical profiling techniques to provide new insights into the involvement of RAS in aneurysm genesis. A prospective, single-center study was conducted between October 2023 and July 2024. Serum Ang metabolite levels were measured using RAS Fingerprint technology. Aortic tissue samples were analyzed for local RAS activity, including Ang levels and enzyme activity. Additionally, pre- and postoperative serum samples were obtained in a select group of patients. In total, 37 aneurysm patients and 56 controls were included. Aneurysm patients exhibited higher systemic levels of nearly all Ang metabolites compared to controls, with significant differences in Ang I ( p = 0.002), Ang II ( p = 0.047), Ang 1-5 ( p = 0.004), and Renin ( p = 0.014) in patients without pharmacological RAS interference. Aneurysm patients receiving ACE inhibitors showed lower serum concentrations in ACE2 activity ( p = 0.042) and increased Ang IV levels ( p = 0.049) compared to controls. Postoperative measurements indicated different dynamics regarding angiotensin metabolite changes in patients with or without ACE inhibition. This study provides the first comprehensive characterization of RAS profiles in aneurysm patients. These findings add to the body of evidence regarding associations between of RAS and the pathogenesis of arterial aneurysms.

The circulating renin-angiotensin system (RAS) is an endocrine system with key functions in maintaining blood pressure, fluid volume, and electrolytes. The RAS in the kidney (intrarenal RAS) plays a critical role in the onset and progression of kidney diseases. However, the mechanism underlying the onset and progression of diabetic nephropathy in relation to the expression and secretion of angiotensinogen (AGT) in the kidneys remains unclear. In this review, we present an overview of the intrarenal RAS and its role in diabetic nephropathy, as well as reviewing the evidence for the use of urinary AGT as a biomarker of this system in diabetic nephropathy. We also describe the roles of isoflavones in the context of diabetic nephropathy. The considered studies show that the intrarenal RAS-especially AGT-plays a diversified role in diabetic nephropathy; for instance, the increase in AGT due to oxidative stress is suppressed by polyphenols with antioxidant capacity, which is thought to affect the progression of diabetic nephropathy. Therefore, clarification of how polyphenols affect the onset and progression of diabetic nephropathy may provide insights into new treatments for this illness.

Angiotensin II (Ang II) is the most active peptide hormone produced by the renin-angiotensin system (RAS). Genetic deletion of genes that ultimately restrict Ang II formation has been shown to result in marked anemia in mice. In this study, adult mice with a genetic deletion of the RAS precursor protein angiotensinogen (Agt-KO) were used. Experimental analyses included capillary hematocrit, hemogram, plasma and tissue iron quantifications, expression analyses of genes encoding relevant proteins for body iron homeostasis in different organs, as well as plasma and urine hepcidin quantifications. As previously reported, Agt-KO were anemic with reduced red blood cell counts. Interestingly, we found that they presented microcytic anemia based on the reduced red blood cell volume. In agreement, plasma quantification of iron revealed lower levels of circulating iron in Agt-KO. The major body iron stores, namely in the liver and spleen, were also depleted in the RAS-deficient line. Hepatic hepcidin expression was reduced, as well as one of its major regulators, BMP6, as a result of the iron deficiency. However, plasma hepcidin levels were unexpectedly increased in Agt-KO. We confirm the typical morphological alterations and impaired renal function of Agt-KO and conclude that hepcidin accumulates in the circulation due to the reduced glomerular filtration in Agt-KO, and therefore identified the culprit of iron deficiency in Agt-KO. Collectively, the data demonstrated that the severe anemia developed in RAS-deficient mice is exacerbated by iron deficiency which is secondary to the renal damage-induced hepcidin accumulation in the circulation., (© 2025 The Author(s).)

Angiotensin Converting Enzyme 2 (ACE2) was discovered 25 years ago as a negative regulator of renin-angiotensin system, opposing the effects of angiotensin-II. Beyond its well-demonstrated roles in cardiovascular regulation and Covid-19 pathology, ACE2 is involved in a plethora of physio-pathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in β cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia and suggests that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice, a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level, dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, while at the hepatic level, ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications which are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in specific cellular- and tissue-manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders.

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

Background and Aims: Diabetic nephropathy (DN) is an important complication of diabetes, leading to end-stage renal disease (ESRD) worldwide. This review aimed to explore the role of the renin-angiotensin system (RAS) in DN, highlighting current treatments and emerging therapeutic perspectives., Methods: We conducted a narrative review of the literature up to March 2024, focusing on the classical and alternative RAS axes, their implications in DN, and novel therapeutic approaches. Data were sourced from Scopus, PubMed, Scielo, and Cochrane databases., Results: The classical RAS axis, involving angiotensin-converting enzyme (ACE), Angiotensin II (Ang II), and the AT1 receptor, promotes vasoconstriction, sodium retention, and fibrosis in DN. Hyperglycemia-induced Ang II increases oxidative stress, contributing to glomerular hyperfiltration and kidney damage. Current treatments include ACE inhibitors and angiotensin receptor blockers (ARBs), which reduce blood pressure and proteinuria, delaying DN progression. In contrast, the alternative RAS axis, featuring ACE2, Ang-(1-7), and the Mas receptor, offers renoprotective effects by counteracting Ang II actions. Ang-(1-7) reduces inflammation, fibrosis, and podocyte apoptosis. ACE2 activators, Ang-(1-7), and Mas receptor agonists show promise in preclinical studies, reducing glomerular fibrosis and improving renal function. Ang-(1-9) and alamandine may also hold potential in future treatments. Emerging therapies, such as the SGLT2 inhibitors, also demonstrate benefits in reducing DN progression., Conclusion: While ACE inhibitors, ARBs, and SGLT2 inhibitors remain central to DN management, the ACE2-Ang-(1-7)-Mas axis presents a promising therapeutic target. Future research should focus on translating preclinical findings into clinical applications, potentially improving DN treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The gastrointestinal tract plays a vital role in the occurrence and treatment of metabolic diseases. Recent studies have convincingly demonstrated a bidirectional axis of communication between the gut and islets, enabling the gut to influence glucose metabolism and energy homeostasis in animals strongly. The 'gut-islet axis' is an essential endocrine signal axis that regulates islet function through the dialogue between intestinal microecology and endocrine metabolism. The discovery of glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP) and other gut hormones has initially set up a bridge between gut and islet cells. However, the influence of other factors remains largely unknown, such as the homeostasis of the gut microbiota and the integrity of the gut barrier. Although gut microbiota primarily resides and affect intestinal function, they also affect extra-intestinal organs by absorbing and transferring metabolites derived from microorganisms. As a result of this transfer, islets may be continuously exposed to gut-derived metabolites and components. Changes in the composition of gut microbiota can damage the intestinal barrier function to varying degrees, resulting in increased intestinal permeability to bacteria and their derivatives. All these changes contribute to the severe disturbance of critical metabolic pathways in peripheral tissues and organs. In this review, we have outlined the different gut-islet axis signalling mechanisms associated with metabolism and summarized the latest progress in the complex signalling molecules of the gut and gut microbiota. In addition, we will discuss the impact of the gut renin-angiotensin system (RAS) on the various components of the gut-islet axis that regulate energy and glucose homeostasis. This work also indicates that therapeutic approaches aiming to restore gut microbial homeostasis, such as probiotics and faecal microbiota transplantation (FMT), have shown great potential in improving treatment outcomes, enhancing patient prognosis and slowing down disease progression. Future research should further uncover the molecular links between the gut-islet axis and the gut microbiota and explore individualized microbial treatment strategies, which will provide an innovative perspective and approach for the diagnosis and treatment of metabolic diseases., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits angiogenesis, vasopermeability, and vasodilation. Cathepsin D (CTSD) cleaves the N-terminal of PRL to generate vasoinhibin in the retina of neonate mice as revealed by the CTSD inhibitor, pepstatin A. However, pepstatin A also inhibits renin. Because renin is expressed in the retina and the renin-angiotensin system gives rise to peptides with positive and negative effects on blood vessel growth and function, we investigated whether renin cleaves PRL to vasoinhibin in the newborn mouse retina and in the circulation. Newborn mouse retinal extracts from wild-type and CTSD-null newborn mice cleaved PRL to a 14 kDa vasoinhibin and such cleavage was prevented by heat-inactivation, pepstatin A, and the selective renin inhibitor VTP-27999 suggesting the contribution of renin. In agreement, recombinant renin cleaved different species PRLs to the expected 14-kDa vasoinhibin, a mass consistent with a consensus renin cleavage site located at Leu124-Leu125 in rat and mouse PRLs and at Leu126-Leu127 in human, bovine, and ovine PRLs. Dehydration followed by rehydration (D/R) in rats increased the levels of renin and PRL in plasma. Further increase in PRL circulating levels by the dopamine D2 receptor blocker, sulpiride, enabled detection of 14 kDa vasoinhibin in D/R rats. Moreover, the incubation of PRL with plasma from D/R rats generated a 14-kDa vasoinhibin that was prevented by VTP-27999. These findings add renin to the list of PRL-cleaving proteases and introduce vasoinhibin as a putative renin-angiotensin system-mediated mechanism for regulating blood vessel growth and function., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F 1 (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation of APOL1-Mediated Kidney Disease (AMKD). Notably, APOL1RRVs have not consistently been shown to increase the prevalence or severity of diabetic kidney disease (DKD) progression, which is the most common cause of End-Stage Kidney Disease (ESKD). While this apparent discrepancy seems perplexing, its clarification should provide important mechanistic and therapeutic insights. Activation of the Renin-Angiotensin System (RAS) plays a critical role in the development and progression of DKD. Recent in vitro and in vivo studies also demonstrated that RAS activation contributes to kidney cell injury in AMKD experimental models. Both high glucose, as well as APOL1RRVs escalate the podocyte expression of miR193a, a known mediator of glomerulosclerosis, including idiopathic Focal Segmental Glomerular Sclerosis (FSGS) and DKD. We propose that either the RAS and/or miR193a levels in the diabetic milieu are already maximally conducive to kidney target cell injury and, therefore, are agnostic to further injury in response to APOL1RRVs. Similarly, the contributory role of hypertension (which is frequently reported as the second most common cause of ESKD) in the progression of AMKD remains a controversial issue. Since several clinical reports have shown that controlling hypertension does not consistently slow the progression of AMKD, this has led to a formulation wherein APOL1-RRVs primarily lead to kidney injury with accompanying hypertension. Notably, half a decade later, the notion that hypertension is not a cause but rather a consequence of kidney injury was contested by investigators analyzing the Mount Sinai BioMe repository, a comprehensive clinical and genetic database including participants with APOL1RRVs. These investigators observed that hypertension predated the observed decline in GFR in individuals with APOL1RRVs by ten years. In the present study, we discuss the mechanistic forces that may underpin the gaps in these clinical manifestations, which did not allow the temporal association of hypertension with AMKD to be translated into causation and may also dissociate DKD and AMKD. We have hypothesized models that need to be validated in future experimental studies.

Del Nido cardioplegia (DNC), a blood-and-crystalloid solution containing high and low concentrations of potassium and calcium, respectively, is used as a single-dose antegrade infusion to induce immediate cardiac arrest in the surgery of patients with cardiovascular diseases requiring extracorporeal circulation. Adding cardioprotective molecules may further reduce the damage-triggered ischemia/reperfusion (I/R) injury. Angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), members of the counter-regulatory renin-angiotensin system, have shown cardioprotective effects in cardiac hypertrophy and I/R models. This study aimed to evaluate the effects of Ang-(1-9) and Ang-(1-7), as adjuvants of the DNC, on cardioprotection and ventricular function in isolated rat hearts subjected to I/R and in cultured neonatal rat ventricular myocytes subjected to simulated I/R (sI/R). The addition of DNC and Ang-(1-9) and Ang-(1-7) decreased lactic dehydrogenase (LDH) release in cultured cardiomyocytes subjected to sI/R in comparison to those cardiomyocytes subjected to sI/R and incubated with DNC alone. Moreover, hearts treated with Ang-(1-9) during reperfusion after DNC + I/R exhibited fewer arrhythmias and required less time to reach left ventricular developed pressure stability. Overall, reperfusion with DNC and Ang-(1-9) improves the recovery of the left ventricular function of the heart., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can improve muscle function and exercise capacity, as well as preventing, attenuating or reversing age-related losses in muscle mass, however, the exact mechanisms by which these drugs affect muscle cells, are not yet fully elucidated. Moreover, the potential epigenetic alterations induced in skeletal muscle tissue are also largely unexplored. The aim of this study was to evaluate if enalapril or losartan can change the physical performance and epigenetic profile of skeletal muscle in spontaneously hypertensive rats (SHRs). Male SHRs were treated with water, enalapril (10/mg/kg/day) or losartan (10/mg/kg/day) for 28 consecutive days and submitted to progressive testing on a treadmill. Body weight, perigonadal and retroperitoneal fat, mean arterial pressure, heart rate, running distance and global DNA methylation in the gastrocnemius and soleus muscles were evaluated. Enalapril reduced the rate of weight gain, as well as reducing retroperitoneal fat (p < 0.05) and MAP (p < 0.05) and avoiding the decline in running distance when compared to the other groups (p > 0.05), even 7 days after the end of treatment (p > 0.05). Moreover, enalapril increased global DNA methylation in gastrocnemius muscle cells (p < 0.01). No effects were observed in the losartan-treated group. Our data showed that enalapril prevented the decline in physical function in SHR, as well as reduced the rate of weight gain of the animals. In addition, the results showed, alterations in the global DNA methylation of skeletal muscle cells skeletal structures of the gastrocnemius muscle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The importance of the brain renin-angiotensin system in cardiovascular function is well accepted. However, not knowing the precise source of renin in the brain has been a limitation toward a complete understanding of how the brain renin-angiotensin system operates., Methods: Highly sensitive in situ hybridization techniques and conditional knockout mice were used to address the location and function of renin in the brainstem., Results: We identified novel renin-expressing cholinergic neurons in the nucleus ambiguus (NuAm), a major vagal cardioinhibitory center in the brainstem. The expression of renin-angiotensin system genes was relatively abundant in the NuAm, implying that angiotensin II might mediate an important regulatory role in this nucleus and other regions with neural connectivity to the NuAm. Then, we generated conditional knockout mice lacking the classical renin isoform (Ren-a ChAT-KO ), specifically in cholinergic neurons. Ablation of Ren-a in cholinergic neurons abrogated renin expression in the NuAm. Moreover, studies using radiotelemetry, heart rate variability analyses, and pharmacological approaches revealed that the parasympathetic nervous system is depressed in Ren-a ChAT-KO males while augmented in the Ren-a ChAT-KO females. Subsequently, transcriptomic approaches were used to infer putative genes and signaling pathways regulated by renin within the NuAm., Conclusions: This study revealed that renin in cholinergic neurons plays a fundamental role in preserving autonomic balance and cardiovascular homeostasis in a sex-dependent manner. These findings define the NuAm as an endogenous, local source of renin with biological function and serve as conclusive evidence for the presence and functionality of the brain renin-angiotensin system., Competing Interests: None.

Objective: Individuals who have metabolically healthy overweight/obesity (MHOO) do not have cardiometabolic complications despite an elevated BMI. Renin-angiotensin-aldosterone system (RAAS) activation and salt sensitivity of blood pressure (SSBP) are cardiovascular disease (CVD) risks, which are increased in individuals with higher BMI values. Little is known about the differences in RAAS activation and SSBP between MHOO and metabolically unhealthy overweight/obesity (MUOO) phenotypes., Methods: We studied 1430 adults on controlled dietary sodium. Individuals in the MHOO group had BMI ≥ 25 kg/m 2 without comorbidities (e.g., diabetes, dyslipidemia, hypertension, CVD), whereas individuals in the MUOO group had BMI ≥ 25 kg/m 2 and at least one comorbidity. The control group included healthy individuals (BMI 18.5-24.9 kg/m 2 )., Results: BMI was similar between the MHOO (28.9 kg/m 2 ) and MUOO groups (29.3 kg/m 2 ; p = 0.317). On liberal sodium, the MUOO group had activated RAAS compared with the MHOO group, including higher plasma aldosterone concentration (mean [SD], 1.11 [0.48] ng/dL; p = 0.020), plasma angiotensin II levels (4.11 [2.0] pg/mL; p = 0.040), and percentage of individuals with plasma renin activity ≥ 1.0 ng/mL/h (+3.6%; p = 0.017). The MUOO group had higher SSBP than the MHOO group (6.0 [1.9] mm Hg; p = 0.002). Applying a zero-to-six-point metabolic health score found that a worse score was associated with higher measurements of RAAS activity and SSBP (p < 0.001)., Conclusions: Compared to the MHOO group, the MUOO group was characterized by an increase in the following two CVD risk factors: higher RAAS activity and SSBP on controlled sodium diets. Therapeutic interventions targeting the effects of angiotensin II and/or aldosterone may offer cardiometabolic protection for individuals with the MUOO phenotype., (© 2025 The Obesity Society.)

As tissue and intracellular RAS have been reported in different organs and systems. there is local RAS in the ovary, called the ovarian renin-angiotensin system (OVRAS). In this study, we investigated the correlation between RAS (total renin, AngII, Ang1-7), vascular endothelial growth factor (VEGF) and E2 in dominant follicular fluid and ovarian reserve capacity and patient age. Moreover, we analyzed its predictive value for assisted reproductive technology (ART) related outcomes. We observed that the concentrations of VEGF in the follicular fluid of dominant follicles in the ≥ 38 year old group were markedly higher than those in the < 30 year old group (P < 0.05). Total renin and AngII levels were positively correlated with normal fertilization rate (P < 0.05). Ang1-7 levels were positively correlated with the number of mature oocytes, oocyte maturation rate and number of 2PN fertilized cells (P < 0.05). Expressions of VEGF were negatively correlated with number of 2PN fertilized cells, number of D3 embryos for blastocyst culture, number of blastocysts formed, number of available embryos and number of high-quality embryos (P < 0.05). Thus, the expressions of OVRAS (total renin, AngII, Ang1-7 and VEGF) in dominant follicular fluid are correlated with ART outcomes., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: Hypertension depends on renin-angiotensin system dysfunction; however, little is known about its implications in the outcomes of neurogenic hypertension induced by peri-pubertal insults. This study aimed to evaluate whether hypertension induced by a peri-pubertal low-protein diet is related to renin-angiotensin system dysfunction in adult male Wistar rats., Methods and Results: Thirty-day-old male Wistar rats were fed a low-protein diet (4 % casein) for 30 days and subsequently fed a 20.5 % normal protein diet for a 60-day dietary recovery (LP group). Control animals (NP group) were fed a 20.5 % protein diet throughout their lives. Cardiovascular and renin-angiotensin system functions were evaluated on postnatal day 120 (6-24 animals per group). Statistical analyses were performed using the Student's t-test. Animals with LP show increased arterial blood pressure. The angiotensin 2 dose-response curve of LP animals showed an increase in the pressor response at a lower dose (50 ng/kg) and a reduction in the pressor response at a higher dose (400 ng/kg) compared with NP animals. Angiotensin 2 type 1 receptor mRNA levels were increased in the hearts of LP animals; however, angiotensin 2 type 2 receptor and MAS receptor mRNA levels were reduced. In the aorta, AT1 and AT2 mRNA levels were increased in LP animals, whereas MAS receptor mRNA levels were decreased in comparison to NP animals., Conclusion: The renin-angiotensin system is disrupted in hypertension induced by protein restriction exposure during peri-pubertal life., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The Renin-Angiotensin System (RAS) is a complex neuroendocrine system consisting of a single precursor protein, angiotensinogen (AGT), which is processed into various peptide hormones, including the angiotensins [Ang I, Ang II, Ang III, Ang IV, Ang-(1-9), Ang-(1-7), Ang-(1-5), etc] and Alamandine-related peptides [Ang A, Alamandine, Ala-(1-5)], through intricate enzymatic pathways. Functionally, the RAS is divided into two axes with opposing effects: the classical axis, primarily consisting of Ang II acting through the AT 1 receptor (AT 1 R), and in contrast the protective axis, which includes the receptors Mas, AT 2 R and MrgD and their respective ligands. A key area of RAS research is to gain a better understanding how signaling cascades elicited by these receptors lead to either "classical" or "protective" effects, as imbalances between the two axes can contribute to disease. On the other hand, therapeutic benefits can be achieved by selectively activating protective receptors and their associated signaling pathways. Traditionally, robust "hypothesis-driven" methods like Western blotting have built a solid knowledge foundation on RAS signaling. In this review, we introduce untargeted mass spectrometry-based phosphoproteomics, a "hypothesis-generating approach", to explore RAS signaling pathways. This technology enables the unbiased discovery of phosphorylation events, offering insights into previously unknown signaling mechanisms. We review the existing studies which used phosphoproteomics to study RAS signaling and discuss potential future applications of phosphoproteomics in RAS research including advantages and limitations. Ultimately, phosphoproteomics represents a so far underused tool for deepening our understanding of RAS signaling and unveiling novel therapeutic targets., (© 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Objectives: To analyze maternal and perinatal outcomes and serum levels of the preeclampsia (PE) biomarkers sFlt-1 and PlGF in pregnant women with hypertensive disorders vaccinated against SARS-CoV-2, with or without confirmed COVID-19 during pregnancy., Methods: Multicenter (two-center) prospective cohort study secondary analysis. The cohort comprised pregnant women with hypertensive disorders who received SARS-CoV-2 vaccination, assessed from August 2021 to December 2022. Key variables included sociodemographic information, clinical background, maternal and perinatal outcomes, and biomarkers serum concentrations. A sFlt-1/PlGF ratio ≥ 38 was the threshold for predicting PE. The study compared outcomes based on the timing of SARS-CoV-2 infection and PE clinical onset., Results: For biomarker analysis, 170 women provided serum samples: 31 had a confirmed COVID-19 during pregnancy, while 139 did not. Among these 170 women, 86 had chronic hypertension, and 100 developed PE. There were no significant differences in sociodemographic characteristics and gestational outcomes between the groups. The dynamics of the sFlt-1/PlGF ratio were similar regardless of COVID-19. Cesarean delivery was the most common delivery method in both groups, and there was a high rate of preterm births. No neonatal or maternal deaths were recorded., Conclusions: The study suggests that pregnant women with hypertensive disorders who have been vaccinated against SARS-CoV-2 and subsequently infected show comparable maternal and perinatal outcomes and PE biomarker levels to those who were not infected. These results suggest that SARS-CoV-2 vaccination is protective for pregnant women, potentially reducing the association with a PE-like syndrome in severe cases of COVID-19 among those who are unvaccinated., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IUM serves on the scientific advisory board of Seed Health., (Copyright © 2025 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Renal ischaemia due to renal artery stenosis produces two differing responses - a juxtaglomerular hypertensive response and cortical renal dysfunction. The reversibility of renal impairment is not predictable, and thus renal revascularisation is controversial. This study aims to test the hypothesis that the hypertensive response to renal ischaemia reflects viable renal parenchyma, and thus could be used to predict the recovery in renal function. A retrospective analysis was performed of all patients who had renal revascularisation for renal impairment in a defined geographical area (West of Scotland, population 2.4 million) between 2008 and 2024. Clinical records were used to determine the pre-intervention blood pressure, anti-hypertensive medication load and renal function, and post-intervention outcomes. The Hypertensive Index (HTi), a combined measure of systolic blood pressure and antihypertensive drug load, was used as a measure of pre-intervention hypertensive response. 75 patients had intervention for renal impairment over 15 years (68 endovascular, 7 open). Mean pre-intervention serum creatinine of 323 µmol/L was reduced to 191 umol/L at discharge and 182 µmol/L at 6-month follow-up. Refractory hypertension (HTi > 120) was associated with a significant benefit from revascularisation with improved renal function (p = 0.003) and reduced risk of future dialysis (p = 0.001). Renal impairment with no hypertensive response was highly predictive of the need for future dialysis. The hypertensive index is a good predictor of the impact of renal revascularisation on improving renal function with good outcomes in selected patients, and the absence of this is an indicator of chronic non-reversible renal dysfunction., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: CD is funded by the British Heart Foundation (Centre of Research Excellence Award, reference RE/18/6/34217). All other authors declare no conflict of interest. Ethics statement: All participants provided written informed consent and all study procedures were in concordance with the Declaration of Helsinki, 1975 (revised 2000). Formal ethical approval for this retrospective study was not required as per national legislation produced by the Health Research Authority., (© 2025. The Author(s).)

Objective: To characterise patients with heart failure (HF) in Primary Health Care (PHC) and describe their socio-demographic and clinical characteristics and pharmacological treatment., Design: Descriptive cohort study. SITE: Information System for the Development of Research in Primary Care (SIDIAP), which captures information from the electronic health records of PHC of the Catalan Institute of Health (approximately 80% of the Catalan population)., Participants: Adults with an active diagnosis of HF between 2018 and 2022., Main Measurements: Sociodemographic and anthropometric variables, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA), laboratory data, comorbidities, exposure to drugs for HF and other pathologies., Results: 75,769 individuals were included; 22.7% with HF with reduced LVEF (HFrEF), 26.2% with preserved LVEF (HfpEF) and 51.2% with non-specific HF. The HfrEF group consisted mostly of men (59.5%), with a mean age of 74.8 years, and the others of women (58.8% and 54.6%, aged 78.7 and 80.6 years, respectively). LVEF was recorded in 20.3% and NYHA in 43.9% of patients. In terms of treatment, 75.3% of people with HfrEF were receiving renin-angiotensin system (RAS) drugs, 75.9% beta-blockers, 42.1% mineralocorticoid receptor antagonists, 33.6% sodium-glucose cotransporter type 2 inhibitors and 62.8% diuretics. 63% with HfpEF were receiving RAS and 68% diuretics. 61.8% with unspecified HF were receiving RAS and 67.5% diuretics., Conclusions: We analysed the population with HF in PHC in Catalonia. We highlight a low registry of cardiac function, LVEF and NYHA. The frequency of drug use for HF was different between populations and differed from the recommendations., (Copyright © 2024 The Author(s). Publicado por Elsevier España S.L.U. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) associated with coronavirus infectious disease (COVID)-19 has been a challenge in intensive care medicine for the past three years. Dysregulation of the renin-angiotensin system (RAS) is linked to COVID-19, but also to non-COVID-19 ARDS. It is still unclear whether changes in the RAS are associated with prognosis of severe COVID-19., Methods: In this prospective exploratory study, blood samples of 94 patients with COVID-19 were taken within 48 h of admission to a medical ward or an ICU. In ICU patients, another blood sample was taken seven days later. Angiotensin (Ang) I-IV, Ang 1-7, Ang 1-5 and aldosterone concentrations were measured with liquid chromatography tandem mass spectrometry (LC-MS/MS) followed by calculation of markers for activities of renin (PRA-S) and ACE (ACE-S), alternative RAS activation (ALT-S) as well as the ratio of aldosterone to Ang II (AA2R). Angiotensin-converting enzyme (ACE) and ACE2 concentrations were measured by LC-MS/MS-based assays. All RAS parameters were evaluated as predictors of 28-day and 60-day survival using receiver operating characteristic and multivariate logistic regression analysis., Results: AA2R at inclusion was a predictor of 60-day survival for ICU patients with an AUROC of 0.73. Ang II and active ACE2 were inversely associated with survival (OR 0.07; 95%CI 0.01, 0.39 and OR 0.10; 95%CI 0.01, 0.63) while higher Ang 1-7 predicted favorable outcome (OR 6.8; 95%CI 1.5, 39.9). ICU patients showed higher concentrations of all measured angiotensin metabolites, PRA-S, ALT-S and active ACE2, and lower ACE-S and AA2R than patients in the medical ward at inclusion. After seven days in the ICU, Ang I, Ang II, Ang III and Ang IV concentrations decreased, while ACE and ACE2 levels increased. Ang I, PRA-S, Ang 1-7 and Ang 1-5 concentrations correlated with the SOFA score both at the time of inclusion and after seven days, and driving pressure after seven days., Conclusions: AA2R at inclusion predicted 60-day survival with moderate sensitivity, revealing a dissociation between unchanged aldosterone and increased Ang II levels in the most severely ill COVID-19 patients. After adjustment for confounders, Ang 1-7 as the final metabolite of alternative RAS was predictive for survival., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol “Exploratory study of the angiotensin metabolite profile in blood as marker for prognosis in COVID-19” was reviewed and approved by the ethics committee of the Medial University of Vienna (EK Nr. 1328/2020 on April 11th, 2020). Informed consent was obtained from all study participants according to the Austrian legislation regulating the consent of conscious and nonconscious patients participating in clinical trials. Consent for publication: Not applicable. Competing interests: KK reports travel expenses from Biotest GmbH and grants from Apeptico GmbH, Biotest GmbH, Alterras Therapeutics GmbH and Bayer AG. OD is a shareholder and employee of Attoquant Diagnostics GmbH. MP is founder, shareholder and former employee of Attoquant Diagnostics GmbH. RU reports travel expenses and honoraria from Biotest GmbH, grants from CCORE, a patent (EP 151897774, minimally invasive liquid lung), and holds equity in CCORE Technology, a medical device company that develops minimally invasive blood purification devices. The other coauthors have no conflicts of interest to declare., (© 2025. The Author(s).)

Drug development for human disease relies on preclinical model systems such as human cell cultures and animal experiments before therapeutic treatments can ultimately be tested on humans in clinical studies. We here describe the generation of a novel human cell line (HLMVEC/SVTERT289) that we generated by transfection of microvascular endothelial cells from healthy donor lung tissue with the catalytic domain of telomerase and the SV40 large T/small t-antigen. These cells exhibited satisfactory growth characteristics and largely maintained their native characteristics, including morphology, cell surface marker expression, angiogenic potential and the protein composition of secreted extracellular vesicles. In order to test their suitability as a disease model, we simulated mechanical stress induced by cyclic stretch as encountered in ventilator-induced lung injury using the FlexCell ® system and compared their performance to primary lung endothelial cells. In this setting, HLMVEC/SVTERT289 cells exhibited significantly higher neprilysin activity on the cell surface and extracellular vesicles secreted from the cell line exhibited higher Tissue Factor and ACE2 expression but lower ACE expression and ACE activity than vesicles released from the primary cells. This study provides an unprecedented and detailed characterization of the HLMVEC/SVTERT289 cell line, which should help to appraise its suitability in different molecular studies.

Aldosterone, the primary adrenal mineralocorticoid hormone, as an integral part of the renin-angiotensin-aldosterone system (RAAS), is crucial in blood pressure regulation and maintaining sodium and potassium levels. It interacts with the mineralocorticoid receptor (MR) expressed in the kidney and promotes sodium and water reabsorption, thereby increasing blood pressure. However, MRs are additionally expressed in other cells, such as cardiomyocytes, the endothelium, neurons, or brown adipose tissue cells. Therefore, aldosterone (especially aldosterone excess) may have other major impacts besides simply regulating blood pressure and circulating ion balance. Recent studies have reported a non-hypertensive impact on the cardiovascular, immune, and metabolic systems, a pro-oxidant effect, and a pro-fibrotic effect. In this review, we emphasise the non-hypertension-related effects of aldosterone, including advances in our understanding of the cellular mechanisms by which aldosterone mediates its cellular effects. We also summarise potential clinical complications related to both the hypertensive and non-hypertensive effects of aldosterone.

Background: Pancreatic Cancer (PC) is one of the most malignant tumors and highly invasive neoplasms around the world., Objective: This systematic review and meta-analysis aims to study the relationship between the use of renin-angiotensin-aldosterone system inhibitors and the incidence and mortality of PC., Methods: The electronic search was conducted systematically until October 10, 2023. in databases, including Scopus, Web of Science (WOS), PubMed/MEDLINE, Cochrane Library, and Embase. The required data were extracted from the articles and were analyzed by Stata 15 using statistical tests (Chi-square and I 2 ), Forest plots, and publication bias tests (Begg's and Egger's tests)., Results: A total of four studies (2011-2019; n=314,856) investigated the relationship between RAS antagonists and PC risk. No significant associations were found between angiotensin receptor blockers (ARBs) (OR=0.94, 95% CI: 0.77-1.14, p=0.513), angiotensin-converting enzyme inhibitors (ACEIs) (OR=0.96, 95% CI: 0.84-1.09, p=0.505), or combination therapy (ARBs + ACEIs) (OR=0.97, 95% CI: 0.87-1.09, p=0.627) and PC risk. Also, nine studies (2010-2023; n=20,483) examined the association between renin-angiotensin-aldosterone system inhibitors and PC mortality. Significant reductions in PC mortality were found for ARBs (OR=0.81, 95% CI: 0.66-0.98, p=0.032), ACEIs (OR=0.89, 95% CI: 0.80-0.99, p=0.038), and combination therapy (OR=0.83, 95% CI: 0.70-0.97, p=0.022). No evidence of publication bias was found in the study results., Conclusion: In summary, while renin-angiotensin-aldosterone system inhibitors did not appear to impact PC risk, their use was associated with lower PC mortality based on this meta-analysis of the current evidence. More rigorous and well-designed studies are required to validate and support these findings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT 1 and AT 2 ) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT 1 , AT 2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction/objective: Emotional, mental, or psychological distress, defined as increased symptoms of depression, anxiety, and/or stress, is common in patients with chronic diseases, such as cardiovascular (CV) disease (CVD)., Methods: Literature was reviewed regarding data from studies and meta-analyses examining the impact of emotional stress on the occurrence and outcome of several CVDs (coronary disease, heart failure, hypertension, arrhythmias, stroke). These influences' pathophysiology and clinical spectrum are detailed, tabulated, and pictorially illustrated., Results: This type of stress is a newly recognized risk and prognosticator for CVD including coronary artery disease, heart failure, hypertension, cardiac arrhythmias, and stroke, independently of conventional risk factors. It can impact CV outcomes, and also affect health care utilization, with more patient visits to health care facilities. The biological systems activated by mental stress comprise the sympathetic nervous system (SNS), the renin-angiotensin system (RAS), and the hypothalamic- pituitary-adrenal (HPA) axis, while several other biological processes are disrupted, such as endothelial function, inflammatory responses, oxidative stress, mitochondrial function and the function of the amygdala which is the central nervous system processing center of emotions and emotional reactions., Conclusion: Emotional stress that aggravates symptoms of depression, anxiety, and/or perceived mental stress is common in patients with chronic diseases, such as CVD. It is a newly recognized risk and prognosticator for several CVDs. It can influence CV outcomes, and also affect health care utilization. The biological systems activated by mental stress comprise the SNS, the RAS, and the HPA axis, while several other biological processes are disrupted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2024 John Wiley & Sons Ltd.)

Hypertension stands out as a substantial independent risk factor in the progression of chronic kidney disease; however, the exact pathological mechanisms remain elusive. Our preliminary studies find that Wnt/β-catenin control renin-angiotensin system (RAS) expression, thus playing an important role in the pathogenesis of hypertension and renal fibrosis. As an integral component of the RAS, the (pro)renin receptor (PRR) plays a crucial role in the activation of the RAS and hypertension. Recent studies suggest a reciprocal relationship between PRR and Wnt/β-catenin signaling, potentially contributing to hypertensive renal fibrosis development. To assess the role of PRR in mediating hypertensive nephropathy, we manipulated this signaling by over expression of PRR ligand or blockade of PRR by siPRR. In vivo, PRR induction promoted hypertension, proteinuria, renal fibrosis, inflammatory response and β-catenin activation in Ang II induced hypertension mice. Conversely, blockade of PRR inhibited Ang II mediated hypertension, renal fibrosis and inflammation. In vitro, PRR over expression renal tubular cells exacerbated the Ang II induced fibrotic response and inflammation. Moreover, PRR was upregulated in hypertensive nephropathy patients, and correlated with renal function and renal fibrosis. These results indicate that PRR interact with Wnt/β-catenin signaling promote the progression of hypertensive nephropathy. PRR could be served as a biomarker for the diagnosis and treatment of hypertensive renal fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous studies showed that preeclampsia (PE) amplifies cardiovascular dysfunction induced by endotoxemia in adult male, but not female, offspring. Here, we asked if such aggravated endotoxic insult could be nullified by modulators of the renin-angiotensin system (RAS). PE was induced by gestational administration of N ω -nitro-L-arginine methyl ester(L-NAME, a nitric oxide synthase inhibitor). Adult male offspring of PE mothers treated gestationally with angiotensin 1-7 (Ang1-7, angiotensin II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (peroxisome proliferator-activated receptor gamma, PPARγ, agonist), or combined losartan/pioglitazone were instrumented with femoral indwelling catheters and challenged intravenously with a 5-mg/kg dose of lipopolysaccharides (LPS, 5 mg/kg). LPS caused significant decreases in blood pressure (BP) and spectral index of overall heart rate variability and increases in heart rate and left ventricular contractility (dP/dtmax). These effects were mostly reduced to similar magnitudes by individual drug therapies. In offspring born to Ang1-7-treated dams, the spectral index of cardiac sympathovagal balance showed elevated sympathetic dominance in response to LPS. Immunohistochemistry revealed that Ang1-7, but not losartan/pioglitazone, abolished the exaggerated increases in toll-like receptor 4 (TLR-4) expression caused by PE/LPS in heart tissues and neuronal circuits of brainstem rostral ventrolateral medulla (RVLM). By contrast, the losartan/pioglitazone regimen, but not Ang1-7, decreased and increased angiotensin converting enzyme (ACE) and ACE2 expression, respectively. Together, gestational fetal reprogramming of Ang II (depression) and Ang1-7 (activation) arms of RAS effectively counterbalance worsened endotoxic cardiovascular and inflammatory profiles in adult male offspring of PE rats., Competing Interests: Declarations. Ethics approval: All experiments were performed in strict accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for animal experiments and guidelines of the Animal Care and Use Committee of the Faculty of Pharmacy, Alexandria University, Egypt (Approval No. AU0620191113262). All efforts were made to minimize animal suffering, and to reduce the number of animals used. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The renin angiotensin system (RAS) is implicated in various cognitive processes relevant to anxiety. However, the role of the RAS in pattern separation, a hippocampal memory mechanism that enables discrete encoding of similar stimuli, is unclear. Given the proposed role of this mechanism in overgeneralization and the maintenance of anxiety, we explored the influence of the RAS on mnemonic discrimination, i.e., the behavioral ability arising from pattern separation., Design: In a double-blind experimental medicine trial, we examined the effect of losartan, an angiotensin receptor blocker, on mnemonic discrimination in N = 60 healthy volunteers aged 18-50. Participants were randomly allocated to a 50 mg losartan or placebo condition, and then completed the Mnemonic Similarity Task (MST), an established measure of mnemonic discrimination. Main outcome measures were the lure discrimination index (LDI), calculated as the rate of 'similar' responses to lures minus 'similar' responses to foils, and recognition (REC) memory, calculated as the difference between the rate of 'old' responses to targets minus 'old' responses to foils., Results: Data were available for N = 56 participants (N = 40 females, N = 16 males). Participants in the losartan group (N = 29) achieved significantly higher LDI scores (t(54) = 2.30, p = 0.025) compared to the placebo group (N = 27), indicating better mnemonic discrimination. No significant group differences were found in REC scores (U = 324, z = -1.10, d = 0.08; p = 0.271)., Conclusions: We demonstrate for the first time that losartan improves mnemonic discrimination in healthy individuals, suggesting that the RAS may influence pattern separation and anxiety., Competing Interests: Declaration of competing interest SC has provided consultation services and/or served on advisory boards for Boehreinger Ingelheim, Guidepoint and TCG Crossover. The other authors declare no competing interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

The complex relationship between chronic kidney disease (CKD) and neuroinflammation shows how important immunological processes are in mediating cognitive dysfunction and psychiatric symptoms in this disease. Proinflammatory cytokines and chemokines, such as IL-1β and IL-6, are capable of crossing the blood-brain barrier, and, consequently, may contribute to neuropsychiatric symptoms including anxiety, depression, and cognitive impairment in CKD patients. The peptides of the renin-angiotensin system (RAS), with their dual functions in inflammation and neuroprotection, also highlight the intricate immunological mechanisms operating within the kidney-brain axis. Understanding these immunological pathways is essential for developing targeted interventions to modulate neuroinflammation and improve cognitive outcomes in individuals with CKD. Further research in renal immunology and neuroinflammation holds promise for advancing our understanding of the intricate connections between kidney health, brain function, and immune responses in the context of CKD. This review summarizes the critical role of immunological factors in the pathophysiology of CKD-related cognitive impairment and psychiatric disorders., Competing Interests: Conflict of Interest No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning the modulation of its glutamatergic neurotransmission as a promising therapeutic target. Our recently published findings indicate that AT 1 receptor activation enhances NMDAR activity in layer V pyramidal neurons of the rat PFC. At the same time, it suggests that alternative angiotensin pathways, presumably involving AT 4 receptors (AT4Rs), might exert inhibitory effects. Angiotensin IV (Ang IV) and its analogs have demonstrated cognitive benefits in animal models of learning and memory deficits., Methods: Immunohistochemistry and whole-cell patch-clamp techniques were used to map the cell-type-specific localization of AT4R, identical to insulin-regulated aminopeptidase (IRAP), and to investigate the modulatory effects of Ang IV on NMDAR function in layer V pyramidal cells of the rat PFC., Results: AT4R/IRAP expression was detected in pyramidal cells and GABAergic interneurons, but not in microglia or astrocytes, in layer V of the PFC in 9-12-day-old and 6-month-old rats. NMDA (30 μM) induced stable inward cation currents, significantly inhibited by Ang IV (1 nM-1 µM) in a subset of pyramidal neurons. This inhibition was reproduced by the IRAP inhibitor LVVYP-H7 (10-100 nM). Synaptic isolation of pyramidal neurons did not affect the Ang IV-mediated inhibition of NMDA currents., Conclusions: Ang IV/IRAP-mediated inhibition of NMDA currents in layer V pyramidal neurons of the PFC may represent a way of regulating cognitive functions and thus a potential pharmacological target for cognitive impairments and related neuropsychiatric disorders.

The octapeptide angiotensin II (Ang II) is a circulating hormone as well as a locally formed agonist synthesized by the angiotensin-converting enzyme (ACE) of endothelial cells. It forms a powerful mechanism to control the amount and pressure of body fluids. All main effects are directed to save body salt and water and ensure blood pressure under basic conditions and in emergencies. All blood vessels respond to stimulation by Ang II; the immediate response is smooth muscle contraction, increasing vascular resistance, and elevating blood pressure. Such effects are conveyed by type 1 angiotensin receptors (AT 1 Rs) located in the plasma membrane of both endothelial and vascular smooth muscle cells. AT 1 Rs are heterotrimeric G protein-coupled receptors (GPCRs), but their signal pathways are much more complicated than other GPCRs. In addition to G q/11 , the G 12/13 , JAK/STAT, Jnk, MAPK, and ERK 1/2, and arrestin-dependent and -independent pathways are activated because of the promiscuous attachment of different signal proteins to the intracellular G protein binding site and to the intracellular C terminal loop. Substantial changes in protein expression follow, including the intracellular inflammation signal protein NF-κB, endothelial contact proteins, cytokines, matrix metalloproteinases (MMPs), and type I protocollagen, eliciting the inflammatory transformation of endothelial and vascular smooth muscle cells and fibrosis. Ang II is an important contributor to vascular pathologies in hypertensive, atherosclerotic, and aneurysmal vascular wall remodeling. Such direct vascular effects are reviewed. In addition to reducing blood pressure, AT 1 R antagonists and ACE inhibitors have a beneficial effect on the vascular wall by inhibiting pathological wall remodeling.

The renin-angiotensin system (RAS) is a classically known circulatory regulatory system. In addition to the previously known multi-organ circulatory form of the RAS, the existence of tissue RASs in individual organs has been well established. Skeletal muscle has also been identified as an organ with a distinct RAS. In recent years, the effects of RAS activation on skeletal muscle have been elucidated from several perspectives: differences in motor function due to genetic polymorphisms of RAS components, skeletal muscle dysfunction under conditions of excessive RAS activation such as heart failure, and the effects of the use of RAS inhibitors on muscle strength. In addition, the concept of the RAS itself has recently been expanded with the discovery of a 'protective arm' of the RAS formed by factors such as angiotensin-converting enzyme 2 and angiotensin 1-7. This has led to a new understanding of the physiological function of the RAS in skeletal muscle. This review summarizes the diverse physiological functions of the RAS in skeletal muscle and considers the potential of future therapeutic strategies targeting the RAS to overcome problems such as sarcopenia and muscle weakness associated with chronic disease., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Juxtaglomerular (JG) cells are sensors that control blood pressure and fluid-electrolyte homeostasis. In response to a decrease in perfusion pressure or changes in the composition and/or volume of the extracellular fluid, JG cells release renin, which initiates an enzymatic cascade that culminates in the production of angiotensin II (Ang II), a potent vasoconstrictor that restores blood pressure and fluid homeostasis. In turn, Ang II exerts a negative feedback on renin release, thus preventing excess circulating renin and the development of hypertension. How Ang II suppresses renin release from JG cells remains elusive. Ang II may inhibit renin release via increased systemic pressure sensed by JG cells, or through a direct effect on Ang II receptors in JG cells, which in turn mediate intracellular calcium (Ca 2+ ) mobilization, a known suppressor of renin release. However, the intricate cellular events mediating Ca 2+ -induced renin inhibition by Ang II are not fully understood. Further, the unique structural organization of the juxtaglomerular apparatus (JGA), with JG cells clustered around afferent arterioles, suggests complex intercellular interactions, potentially facilitating coordinated Ca 2+ activity in response to Ang II. Here, we investigate the cellular processes that control Ca 2+ mobilization and the signaling mechanisms elicited when JG cells are stimulated with Ang II within the intact anatomical context of the JGA. By examining these processes, we aim to elucidate the role of cellular organization in Ca 2+ -mediated signaling and its impact on renin regulation within the JGA., Objective: To define intra- and inter-cellular Ca 2+ dynamics, identify the driving ion channels, and elucidate their functional role in Ang II-stimulated JG cells within the native kidney structure., Methods and Results: We generated mice expressing JG cell-specific GCaMP6f, a genetically encoded Ca 2+ indicator, under the Ren1 c promoter. Ex vivo Ca 2+ imaging in acutely prepared kidney slices revealed that JG cells within clusters exhibit coordinated, robust Ca 2+ oscillations in response to Ang II stimulation, contrary to previous observations in isolated cells. These oscillations showed dose-dependent increases in occurrence and correlated with suppressed renin secretion. Pharmacological inhibition identified key drivers of these oscillations: endoplasmic reticulum Ca 2+ storage and release, extracellular Ca 2+ uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions alleviated Ang II inhibition of renin secretion., Conclusion: In intact kidney slices, Ang II elicits synchronized Ca 2+ oscillations in JG cells, driven by endoplasmic reticulum-derived Ca 2+ release, ORAI channels, and gap junctions, leading to suppressed renin secretion., Competing Interests: Competing interests The authors declare no competing interest.

Background: Inhibitors of the renin-angiotensin-aldosterone system (RAAS), such as ACE inhibitors (ACEi), angiotensin-II receptor blockers and mineralocorticoid receptor antagonists, reduce morbidity and mortality in hypertension, congestive heart failure and chronic kidney disease. However, their use can lead to hyperkalaemia. We examined the proportions of RAAS inhibitor (RAASi) reduction or withdrawal, across GFR strata, following hospitalisation and the effect on patient mortality., Methods: This was a retrospective cohort study of adult patients hospitalised from 1 January2017 to 31 December2020. Biochemistry data, clinical notes and medicines use were extracted using the CogStack platform, from electronic health records. Patients were identified by creatinine measurement during hospitalisation. Hyperkalaemia was defined as potassium > 5.0 mmol/L, with severity categorisation. RAASi discontinuation defined as ≥ 48 h without administration. Mortality risk associated with RAASi cessation was assessed using Cox proportional hazards models., Results: Among 129,172 patients with potassium measurements, 49,011 were hospitalised. Hyperkalaemia prevalence was 8.57% in the emergency department and 16.79% among hospitalised patients. Higher hyperkalaemia levels correlated with increased CKD and heart failure. RAASi use was more common in hyperkalaemic patients, with higher discontinuation rates during hospitalisation (36% with potassium 5-5.5 mmol/L; 61% with potassium > 6.5 mmol/L). By discharge, 32% of patients had RAASi stopped, and 2% doses reduced. Discontinuation of RAASi was associated with 37% worse survival probability., Conclusion: RAASi cessation was greater with hyperkalaemia and associated with increased mortality in hospitalised patients. Reinstitution of RAASi after hospital discharge, or alternative management of hyperkalaemia if maintained on RAASi therapy, may improve clinical outcomes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The King’s College Hospital Research and Innovation Department, after review of the project, considered this as a service evaluation, rather than research. We confirmed this opinion using the HRA ‘Is this research?’ decision tool ( http://www.hra-decisiontools.org.uk/research/ ). We used anonymous data, at scale, at source (within the hospital IT system), and therefore, patient-level consent was not required. Approval for this approach to use of CogStack is within London—South East Research Ethics Committee approval (18/LO/2048) 2nd January 2019. King's Electronic Patient Record Interface (KERRI) committee (project ID 20210405A) approved the project (within the boundaries of CogStack ethical approval 18/LO/2048) on 7th May 2021. Consent to publish: Not applicable., (© 2024. The Author(s).)

Sodium thiosulfate (STS), a precursor of hydrogen sulfide (H 2 S), has demonstrated antihypertensive properties. Previous studies have suggested that H 2 S-based interventions can prevent hypertension in pediatric chronic kidney disease (CKD). However, the clinical application of STS is limited by its rapid release and intravenous administration. To address this, we developed a poly-lactic acid (PLA)-based nanoparticle system for sustained STS delivery and investigated whether weekly treatment with STS-loaded nanoparticles (NPs) could protect against hypertension in a juvenile CKD rat model. Male Sprague Dawley rats, aged three weeks, were fed a diet containing 0.5% adenine for three weeks to induce a model of pediatric CKD. STS-loaded NPs (25 mg/kg) were administered intravenously during weeks 6, 7, and 8, and at week 9, all rats were sacrificed. Treatment with STS-loaded NPs reduced systolic and diastolic blood pressure by 10 mm Hg and 8 mm Hg, respectively, in juvenile CKD rats. The protective effect of STS-loaded NPs was linked to increased renal expression of H 2 S-producing enzymes, including cystathionine γ-lyase ( CSE ) and D-amino acid oxidase ( DAO ). Additionally, STS-loaded NP therapy restored nitric oxide (NO) signaling, increasing L-arginine levels, which were disrupted in CKD. Furthermore, the beneficial effects of STS-loaded NPs were associated with inhibition of the renin-angiotensin system (RAS) and the enhancement of the NO signaling pathway. Our findings suggest that STS-loaded NP treatment provides sustained STS delivery and effectively reduces hypertension in a juvenile CKD rat model, bringing us closer to the clinical translation of STS-based therapy for pediatric CKD-induced hypertension.

The complex relationship between kidney disease and hypertension represents a critical area of research, yet less attention has been devoted to exploring how this connection develops early in life. Various environmental factors during pregnancy and lactation can significantly impact kidney development, potentially leading to kidney programming that results in alterations in both structure and function. This early programming can contribute to adverse long-term kidney outcomes, such as hypertension. In the context of kidney programming, the molecular pathways involved in hypertension are intricate and include epigenetic modifications, oxidative stress, impaired nitric oxide pathway, inappropriate renin-angiotensin system (RAS) activation, disrupted nutrient sensing, gut microbiota dysbiosis, and altered sodium transport. This review examines each of these mechanisms and highlights reprogramming interventions proposed in preclinical studies to prevent hypertension related to kidney programming. Given that reprogramming strategies differ considerably from conventional treatments for hypertension in kidney disease, it is essential to shift focus toward understanding the processes of kidney programming and its role in the development of programmed hypertension.

Objectives: To summarize evidence regarding intravenous angiotensin II administration in critical illness and provide an updated understanding of its effects on various organ dysfunction and renin-angiotensin system (RAS) biomarkers., Design: A systematic review., Setting: A search of PubMed, Embase, and the Cochrane Library from inception to May 3, 2024. Randomized controlled trials (RCTs), nonrandomized trials, quasi-randomized trials, observational studies, case reports, and case series were included. Comparative studies (RCTs and observational studies with comparator) were used for the main analysis., Participants: Critically ill adults and children., Interventions: Intravenous angiotensin II administration., Measurements and Main Results: Fifty-nine studies with a total of 2,918 participants (5 RCTs, 15 observational studies, and 39 case reports or case series) were analyzed. Septic shock and cardiac surgery were the most common clinical conditions (14 studies for each). In 14 comparative studies (5 RCTs and 9 observational studies), mortality was not different from that in controls, except in 1 observational study. Several studies reported decreased renal replacement therapy use, improved oxygenation and blood pressure response, and decreased rate of myocardial injury with angiotensin II therapy. There was no increase in thrombotic events or adverse events. Angiotensin II therapy reduced renin and angiotensin I levels without affecting other RAS biomarkers., Conclusions: Intravenous angiotensin II has been reported in almost 3000 critically ill patients with diverse types of shock. Despite unclear mortality impacts, angiotensin II seems to confer beneficial effects on several organ systems and RAS derangements, without increasing adverse events., Competing Interests: Declaration of competing interest Y.K. reports receipt of consulting fees from Viatris. A.K.K. reports receipt of consulting fees from Medtronic, Edwards Life Sciences, Philips Research North America, Hillrom, GE Healthcare, Potrero Medical, Viatris, Trevena Pharma, Fifth Eye, Pharmazz, Retia Medical, and Caretaker Medical and a Wake Forest Clinical and Translational Science Institute grant on renin dysfunction in septic shock. A.Z. reports consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, and Fresenius; research funding from Astute-Biomerieux, Fresenius, and Baxter; and speaking fees from Astute-Biomerieux, Fresenius, Baxter, and Paion. R.B. reports grants and consultancy fees from La Jolla Pharmaceuticals, Paion AG, and Viatris. G.L. reports speaking fees from Medis, Paion, and Viatris and consulting fees from Paion and Viatris. All other authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC 50 (10 -4  mol/L) or EC 100 (10 -2  mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC 100 concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with the publication., (Copyright © 2024. Published by Elsevier B.V.)