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Hyperthyroidism is a condition where the thyroid gland produces high levels of thyroid hormone. Heart diseases are one of the main complications of hyperthyroidism. Several studies have shown that losartan (LOS) and diminazene aceturate (DIZE) possess cardioprotection effects against cardiac hypertrophy, ischemic heart disease, and heart failure. The research aimed to investigate the cardioprotection of LOS, DIZE, and their combination in the case of levothyroxine (LT4)-induced cardiomyopathy in rats. Hyperthyroidism was induced by LT4 in drinking water (12 mg/L) for 28 days. LOS (10 mg/kg, orally) and/or DIZE (15 mg/kg, subcutaneously) were administrated in rats with hyperthyroidism for 28 days. Decreased serum creatine kinase myoglobin and lactate dehydrogenase levels and cardiac hypertrophy by DIZE and combination therapy in hyperthyroidism rats have been reported. Cardiac hemodynamic findings showed that DIZE and its combination with LOS decreased the LT4-mediated left ventricular developed pressure (LVDP), rate pressure product (RPP), and RPP recovery percentage. Elevated cardiac oxidative stress and inflammation were confirmed by decreasing cardiac superoxide dismutase (SOD) activity and increasing the total oxidative stress and tumor necrosis factor-alpha (TNF-α) levels. SOD activity and TNF-α level were reversed by LOS and DIZE administration, respectively. Generally, DIZE and combination therapy with LOS improved cardiac dysfunction caused by hyperthyroidism in rats, whereas LOS alone has not been able to effectively respond to this dysfunction. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-aldosterone system inhibitors (RAAS-I) have been shown to prolong overall survival in patients with liver metastasized colorectal cancer in combination with antiangiogenic treatment. The effects of RAAS-I combined with neoadjuvant chemotherapy on colorectal cancer liver metastasis remain unexplored. We aimed to study the response of patients undergoing liver resection to RAAS-I in combination with neoadjuvant therapy to elucidate their potential benefits. Between February 2005 and May 2012, 62 patients fulfilled the inclusion criteria for distant metastasis (cM1) and comparable computed tomography or magnetic resonance tomography scans in the Picture Archiving Communication System of our center before and after neoadjuvant chemotherapy. Follow-up data and clinicopathological characteristics were collected from a prospective database and retrospectively investigated. The chemotherapeutic response to liver metastasis was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria 1.1. Comparing the average reduction of measured lesions, a significant response to chemotherapy was detected in the patients receiving RAAS-I (n = 24) compared to those who did not (n = 38) (P = 0.031). Interestingly, the effect was more distinctive when the size reduction was compared between high responses with more than 50% size reduction of all measured lesions (P = 0.011). In the subgroup analysis of patients receiving bevacizumab treatment, high responses to chemotherapy were observed only in the RAAS-I cohort (28.6% versus 0%, P = 0.022). For neoadjuvantly treated patients, concomitant antihypertensive treatment with RAAS-I showed a higher total size reduction of liver metastasis as a sign of treatment response, especially in combination with antiangiogenic treatment with bevacizumab. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a disease that affects hundreds of millions of people worldwide, is increasing in prevalence in all age groups, including children and adolescents. Much of the morbidity and mortality associated with diabetes is closely related to hypertension, often coincident with diabetes. Comorbid hypertension and diabetes often worsen the outcomes of each other, likely rooted in some overlapping pathogenic mechanisms. In this educational review, we will discuss the shared pathophysiology of diabetes and hypertension, particularly in regard to inflammation and oxidative stress, the sympathetic nervous system, vascular remodeling, and the renin–angiotensin–aldosterone system (RAAS). We will also review current hypertension diagnosis and management guidelines from many international jurisdictions for both adult and paediatric populations in the setting of diabetes. Many of these guidelines highlight the use and utility of RAAS blockers in this clinical scenario; however, on review of the evidence for their use, several meta-analyses and systematic reviews fail to demonstrate superiority of RAAS blockers over other anti-hypertensive medications. Finally, we discuss several new anti-hypertensive medications, review their mechanisms of action, and highlight some of the evidence for their use in the setting of hypertension and diabetes. [ABSTRACT FROM AUTHOR]

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%–7% worldwide and 7%–10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin‐angiotensin‐aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high‐risk patients. Conventional potassium‐binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia–Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at‐risk individuals; and (iii) correction of hyperkalaemia for at‐risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Hyperkalemia (HK) is frequently present in chronic kidney disease (CKD). Risk factors for HK among CKD patients include comorbidities and renin–angiotensin–aldosterone system inhibitor (RAASi) treatment. Current standard of care (SoC) often necessitates RAASi down-titration or discontinuation, resulting in poorer cardiorenal outcomes, hospitalization and mortality. This study evaluates the cost-effectiveness of patiromer for HK in CKD patients with and without heart failure (HF) in an Italian setting. Methods: A lifetime Markov cohort model was developed based on OPAL-HK to assess the health economic impact of patiromer therapy in comparison to SoC after accounting for the effects of HK and RAASi use on clinical events. Outcomes included accumulated clinical events, number needed to treat (NNT) and the incremental cost-effectiveness ratio (ICER). Subgroup analysis was conducted in CKD patients with and without HF. Results: Patiromer was associated with an incremental discounted cost of €4,660 and 0.194 quality adjusted life years (QALYs), yielding an ICER of €24,004. Per 1000 patients, patiromer treatment prevented 275 moderate/severe HK events, 54 major adverse cardiovascular event, 246 RAASi discontinuation and 213 RAASi up-titration/restart. Subgroup analysis showed patiromer was more effective in preventing clinical events in CKD patients with HF compared to those without; QALY gains were greater in CKD patients without HF versus those with HF (0.267 versus 0.092, respectively). Scenario analysis and sensitivity analysis results support base-case conclusions. Conclusion: Patiromer is associated with QALY gains in CKD patients with and without HF compared to SoC in Italy. Patiromer prevented HK events, enabled RAASi therapy maintenance and reduced cardiovascular event risk. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) is a highly potent chemotherapy drug. But its nephrotoxicity poses a significant limitation to its use. The renin-angiotensin system (RAS) has been proposed to play a role in drug-induced nephrotoxicity. This systematic review (SR) sought to identify the link between CDDP-induced nephrotoxicity and the RAS pathway. In this SR, relevant keywords were employed to explore databases such as PubMed (MEDLINE), Scopus (Elsevier), and Institute for Scientific Information (ISI) Web of Science up to October 2023. Nine studies were selected based on predefined inclusion/exclusion criteria. The findings support the involvement of the RAS in the CDDP-induced nephrotoxicity model, along with the activation of inflammatory mediators, lipid peroxidation, and changes in markers of kidney tissue damage. Furthermore, physiology and pathology of RAS-related interventions in CDDP-induced nephrotoxicity models have involved the factors such as human organic cation transporter 2 (hOCT2), organic anion transporting polypeptides 1B1 (OATP1B1) and 1B3, kallikrein-kinin system, and bradykinin receptors. CDDP-induced nephrotoxicity has been found to be substantially influenced by both classic and nonclassic RAS axes. Angiotensin II exacerbates renal damage induced by CDDP. Conversely, inhibiting the pressor arm of RAS in males mitigates this damage. However, activation of the renal vasodepressor arm of RAS exacerbates CDDP-induced nephrotoxicity in females. These findings underscore gender differences in renal function and response to RAS-related interventions in the presence of CDDP. This SR provides insights into both beneficial and adverse interventions associated with RAS in the CDDP-induced nephrotoxicity, offering valuable considerations for researchers and clinicians. [ABSTRACT FROM AUTHOR]

In the first part of this article, the role of intestinal epithelial tight junctions (TJs), together with gastrointestinal dopaminergic and renin–angiotensin systems, are narratively reviewed to provide sufficient background. In the second part, the current experimental data on the interplay between gastrointestinal (GI) dopaminergic and renin–angiotensin systems in the regulation of intestinal epithelial permeability are reviewed in a systematic manner using the PRISMA methodology. Experimental data confirmed the copresence of DOPA decarboxylase (DDC) and angiotensin converting enzyme 2 (ACE2) in human and rodent enterocytes. The intestinal barrier structure and integrity can be altered by angiotensin (1-7) and dopamine (DA). Both renin–angiotensin and dopaminergic systems influence intestinal Na+/K+-ATPase activity, thus maintaining electrolyte and nutritional homeostasis. The colocalization of B0AT1 and ACE2 indicates the direct role of the renin–angiotensin system in amino acid absorption. Yet, more studies are needed to thoroughly define the structural and functional interaction between TJ-associated proteins and GI renin–angiotensin and dopaminergic systems. [ABSTRACT FROM AUTHOR]

Prolylcarboxypeptidase (PRCP, PCP, Lysosomal Pro-X-carboxypeptidase, Angiotensinase C) controls angiotensin- and kinin-induced cell signaling. Elevation of PRCP appears to be activated in chronic inflammatory diseases [cardiovascular disease (CVD), diabetes] in proportion to severity. Vascular endothelial cell senescence and mitochondrial dysfunction have consistently been shown in models of CVD in aging. Cellular senescence, a driver of age-related dysfunction, can differentially alter the expression of lysosomal enzymes due to lysosomal membrane permeability. There is a lack of data demonstrating the effect of age-related dysfunction on the expression and function of PRCP. To explore the changes in PRCP, the PRCP-dependent prekallikrein (PK) pathway was characterized in early- and late-passage human pulmonary artery endothelial cells (HPAECs). Detailed kinetic analysis of cells treated with high molecular weight kininogen (HK), a precursor of bradykinin (BK), and PK revealed a mechanism by which senescent HPAECs activate the generation of kallikrein upon the assembly of the HK–PK complex on HPAECs in parallel with an upregulation of PRCP and endothelial nitric oxide (NO) synthase (eNOS) and NO formation. The NO production and expression of both PRCP and eNOS increased in early-passage HPAECs and decreased in late-passage HPAECs. Low activity of PRCP in late-passage HPAECs was associated with rapid decreased telomerase reverse transcriptase mRNA levels. We also found that, with an increase in the passage number of HPAECs, reduced PRCP altered the respiration rate. These results indicated that aging dysregulates PRCP protein expression, and further studies will shed light into the complexity of the PRCP-dependent signaling pathway in aging. [ABSTRACT FROM AUTHOR]

Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits. [ABSTRACT FROM AUTHOR]

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

Background This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin–angiotensin–aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92–3.41; P  < .0001). Conclusions In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment. [ABSTRACT FROM AUTHOR]

Aims Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin–angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. Methods and results In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10−6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1 , Ammecr1l , Hs6st1 , Nfil3 , Fam221a , Lmo4 , Adamts1 , Cish , Hif3a , Bcl6 , Rad54l2 , Adap1 , Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. Conclusion Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks. [ABSTRACT FROM AUTHOR]

Introduction: Results on the association between the use of renin–angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. Methods: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). Results: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. Conclusions: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear. [ABSTRACT FROM AUTHOR]

Many patients undergoing surgical procedures have a history of hypertension, diabetes mellitus, heart failure, or a combination. Often, these conditions involve the chronic use of a renin–angiotensin system inhibitor, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Observational studies have suggested that continuing ACEIs/ARBs before major noncardiac surgery can increase the risk of intraoperative hypotension, which might drive postoperative complications such as acute kidney injury, myocardial injury, or stroke. Strong recommendations on how to manage ACEIs/ARBs before surgery are, however, lacking owing to insufficient evidence, mostly limited to data from observational studies. Recently, the SPACE trial investigated the impact of preoperative management of ACEIs/ARBs on postoperative myocardial injury. Myocardial injury occurred in 48.3% patients randomised to discontinue and 41.3% patients randomised to continue ACEI/ARB (odds ratio for continuing: 0.77, 95% confidence interval 0.45–1.31). Patients randomised to the 'Stop' group experienced more postoperative hypertension. In a post hoc analysis, patients randomised to the 'Continue' group with low preoperative NT-proBNP concentrations (<100 pg ml−1) experienced less myocardial injury after surgery than the 'Stop' group, whereas no significant difference was observed in patients with elevated preoperative NT-proBNP concentrations. The SPACE trial provides important and new reassuring data on the safety of continuing ACEIs/ARBs before major surgery, challenging previous beliefs. [ABSTRACT FROM AUTHOR]

Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml−1) experience more complications after noncardiac surgery. Individuals prescribed renin–angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L−1 or a ≥5 ng L−1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L−1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml −1) and stopping or continuing RAS inhibitors. Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml −1 (median 339 [160–833] pg ml−1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml−1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml −1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05–5.99); P <0.0001}. For subjects with preoperative NT-proBNP <100 pg ml−1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06–4.65]; P =0.03). For preoperative NT-proBNP >100 pg ml−1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44–2.22]). Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml −1) increased the likelihood of myocardial injury before noncardiac surgery. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the association between missed CMS Star Ratings quality measures for medication adherence over 3 years for diabetes, hypertension, and hyperlipidemia medications (9 measures) and health care utilization and relative costs. STUDY DESIGN: Retrospective cohort study. METHODS: The study examined eligible patients who qualified for the diabetes, statin, and renin-angiotensin system antagonist medication adherence measures in 2018, 2019, and 2020 and were continuously enrolled in a Medicare Advantage prescription drug plan from 2017 through 2021. Atotal of 103,900 patients were divided into 4 groups based on the number of adherence measures missed (3 medication classes over 3 years): (1) missed 0 measures, (2) missed 1measure, (3) missed 2 or 3 measures, and (4) missed 4 or more measures. To achieve a quality measure, patients had to meet the Pharmacy Quality Alliance 80% threshold of proportion of days covered during the calendar year. RESULTS: The mean age of the cohort was 71.1 years, and 49.9% were female. Compared with patients who missed 0 of 9 adherence measures, those who missed 1 measure, 2 or 3 measures, and 4 or more measures experienced 12% to 26%, 22% to 42%, and 24% to 50% increased risks, respectively, of all-cause and diabetes-related inpatient stays and all-cause and diabetes-related emergency department visits (allPvalues<.01). Additionally, patients who missed 1, 2 or 3, and 4 or more adherence measures experienced 14%, 19%, and 20% higher monthly medical costs, respectively. CONCLUSIONS: Missing Star Ratings quality measures for medication adherence was associated with an increased likelihood of health care resource utilization and increased costs for patients taking medications to treat diabetes, hypertension, and hyperlipidemia. [ABSTRACT FROM AUTHOR]

Background: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin–angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. Methods: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. Results: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. Conclusions: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro‐inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang‐(1–7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G‐protein‐coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher‐order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water–electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin–angiotensin–aldosterone system (RAAS) activity, transforming growth factor-β1 (TGF-β1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities. [ABSTRACT FROM AUTHOR]

Objective(s): Preeclampsia (PE) is a complication of pregnancy that might increase progeny risk of cardiovascular and metabolic problems, mainly in males. Renin angiotensin aldosterone system is known to be involved. (Pro) renin/renin receptor ((P)RR) has been shown to participate in cardiovascular pathology. The aim of this work was to evaluate (P)RR expression and function upon cardiovascular and renal tissues from PE dams' offspring. Materials and Methods: We used offspring from normal pregnant and preeclamptic rats, evaluating body, heart, aorta and kidney weight, length, and blood pressure along 3 months after birth. Subsets of animals received handle region peptide (HRP) (0.2 mg/Kg, sc). Another group received vehicle. Animals were sacrificed at first, second, and third months of age, tissues were extracted and processed for immunoblot to detect (P)RR, PLZF, β-catenin, DVL-1, and PKCα. (P)RR and PLZF were also measured by RT-PCR. Results: We found that offspring developed hypertension. Male descendants remained hypertensive throughout the whole experiment. Female animals tended to recover at second month and returned to normal blood pressure at third month. HRP treatment diminished hypertension in both male and female animals. Morphological evaluations showed changes in heart, aorta, and kidney weight, and HRP reverted this effect. Finally, we found that (P)RR, PLZF, and canonical WNT transduction pathway molecules were stimulated by PE, and HRP treatment abolished this increase. Conclusion: These findings suggest that PE can induce hypertension in offspring, and (P)RR seems to play an important role through the canonical WNT pathway and that gender seems to influence this response. [ABSTRACT FROM AUTHOR]

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

Significance: Radiotherapy, which employs ionizing radiation to destroy or prevent the multiplication of tumor cells, has been increasingly used in the treatment of neoplastic diseases, especially cancers. However, radiation collaterally leads to prolonged periods of sperm count suppression, presumably due to impaired spermatogenesis by depleting the germ cell pool, which has long-term side effects for male reproduction. Recent Advances: Studies of antioxidant compounds as a potential strategy for male fertility preservation have been performed mainly from animal models, aiming to prevent and restore the male germinal tissue and its function, particularly against the oxidative stress effects of radiation. Evidence in preclinical and clinical trials has shown that inhibitors of the renin–angiotensin system and other drugs, such as statins and metformin, are candidates for ameliorating radiation-induced damage to several tissues, including the testis and prostate. Critical Issues: Research for developing an ideal radioprotective agent is challenging due to toxicity in the normal tissue, tumor radioresistance, cellular response to radiation, costs, regulation, and timeline development. Moreover, male radioprotection experiments in humans, mainly clinical trials, are scarce and use few individuals. This scenario is reflected in the slow progress of innovation in the radioprotection field. Future Directions: Expanding human studies to provide clues on the efficacy and safety of radioprotective compounds in the human reproductive system is necessary. Drug repurposing, frequently used in clinical practice, can be a way to shorten the development pipeline for innovative approaches for radioprotection or radiomitigation of the repercussions of radiotherapy in the male reproductive system. [ABSTRACT FROM AUTHOR]

Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training. [ABSTRACT FROM AUTHOR]

Background: Hypertension is associated with the risk of prostate cancer (PCa) and its progression, however, it remains unclear whether antihypertensive medicines alter PCa risk or prognosis. This systematic review evaluated the role of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors in the risk and prognosis of PCa. This review was performed in line with PRISMA 2020 guidelines. Methods: Eligible studies comprised peer-reviewed observational studies which reported the role of CCBs and RAS inhibitors in PCa, had accessible full texts, and were written in English. Using a combination of keywords, 5 electronic bibliographic databases which included Web of Science, EMBASE, PubMed, Google Scholar and Scopus were searched. Results: A total of 1,346 studies were retrieved and 18 met the inclusion criteria. Thirteen studies reported reduced or no associated risk, improved prognosis, and survival with the use of RAS inhibitors. Studies on CCBs showed evidence of associated risk of PCa. Data extraction from retrieved studies focused on included study characteristics, setting, authors, year, outcomes of interest, and risk ratios. The quality assessment of included studies by the National Heart, Lung, and Blood Institute study assessment tools, showed that all studies had good quality. Conclusions: The use of RAS inhibitors was mostly associated with lower risks or improved prognosis of PCa. CCBs may also be associated with risks of PCa. This suggests that high-risk patients managed with CCBs should be actively monitored for PCa. However, there is need for further evidence from large-scale prospective, controlled cohort studies to determine any influence of CCBs on PCa. [ABSTRACT FROM AUTHOR]

The pathogenesis and prognosis of patients with acute myocardial infarction (AMI) may be influenced by both genetic and environmental factors. Findings on the relationship of polymorphisms in various genes encoding the renin-angiotensin-aldosterone system with coronary artery lesions and mortality in AMI patients are inconsistent. The aim of this study was to determine whether the AGTR1 A1166C genetic polymorphism affects coronary artery lesions and 1-year mortality in post-AMI patients. Patients with their first AMI admitted to Cho Ray Hospital, Vietnam, from January 2020 to August 2021 were enrolled in this prospective clinical study. All participants underwent invasive coronary angiography and were identified as having the genotypes of AGTR1 A1166C by way of a polymerase chain reaction method. All patients were followed up for all-cause mortality 12 months after AMI. The association of the AGTR1 A1166C polymorphism with coronary artery lesions and 1-year mortality was evaluated using logistic regression and Cox regression analysis, respectively. Five hundred and thirty-one AMI patients were recruited. The mean age was 63.9 ± 11.6 years, and 71.6% of the patients were male. There were no significant differences in the location and number of diseased coronary artery branches between the AA and AC+CC genotypes. The AC and CC genotypes were independently associated with ≥ 90% diameter stenosis of the left anterior descending (LAD) artery (odds ratio = 1.940; 95% confidence interval (CI): 1.059–3.552, p = 0.032). The 1-year all-cause mortality rate difference between patients with the AC and CC genotypes versus those with the AA genotype was not statistically significant (hazard ratio = 1.000, 95% CI: 0.429–2.328, p = 1.000). The AGTR1 A1166C genetic polymorphism is associated with very severe luminal stenosis of the LAD but not with mortality in AMI patients. [ABSTRACT FROM AUTHOR]

Renin is the key enzyme of the systemic renin–angiotensin–aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin‐1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero‐Cre (P0‐Cre) to abrogate Nrp1 constitutively in P0‐Cre lineage‐labelled cells of the kidney. We found that the P0‐Cre precursor cells differentiate into renin‐producing JG cells. We employed a lineage‐tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell‐autonomous role for NRP1 in JG cell function. Nrp1‐deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0‐Cre–expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. Key points: Renin is a centrepiece of the renin–angiotensin–aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney.Neuropilin‐1 (NRP1) is a conserved membrane‐bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression.We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function.Cell‐specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance.The results support the versatility of renin‐producing cells in the kidney and may open new avenues for therapeutic approaches. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the second most common cause of cancer death in the United States, and up to half of patients develop colorectal liver metastases (CRLMs). Notably, somatic genetic mutations, such as mutations in RAS, BRAF, mismatch repair (MMR) genes, TP53, and SMAD4, have been shown to play a prognostic role in patients with CRLM. This review summarizes and appraises the current literature regarding the most relevant somatic mutations in surgically treated CRLM by not only reviewing representative studies, but also providing recommendations for areas of future research. In addition, advancements in genetic testing and an increasing emphasis on precision medicine have led to a more nuanced understanding of these mutations; thus, more granular data for each mutation are reviewed when available. Importantly, such knowledge can pave the way for precision medicine with the ultimate goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. This study's goal was to identify the signaling drivers and pathways that modulate glomerular endothelial dysfunction in DKD via artificial intelligence-enabled literature-based discovery. Cross-domain text mining of 33+ million PubMed articles was performed with SemNet 2.0 to identify and rank multi-scalar and multi-factorial pathophysiological concepts related to DKD. A set of identified relevant genes and proteins that regulate different pathological events associated with DKD were analyzed and ranked using normalized mean HeteSim scores. High-ranking genes and proteins intersected three domains—DKD, the immune response, and glomerular endothelial cells. The top 10% of ranked concepts were mapped to the following biological functions: angiogenesis, apoptotic processes, cell adhesion, chemotaxis, growth factor signaling, vascular permeability, the nitric oxide response, oxidative stress, the cytokine response, macrophage signaling, NF κ B factor activity, the TLR pathway, glucose metabolism, the inflammatory response, the ERK/MAPK signaling response, the JAK/STAT pathway, the T-cell-mediated response, the WNT/ β -catenin pathway, the renin–angiotensin system, and NADPH oxidase activity. High-ranking genes and proteins were used to generate a protein–protein interaction network. The study results prioritized interactions or molecules involved in dysregulated signaling in DKD, which can be further assessed through biochemical network models or experiments. [ABSTRACT FROM AUTHOR]

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

Soluble prorenin receptor (sPRR), a component of the renin-angiotensin system (RAS), has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. Despite studies showing that sPRR in the kidney is produced by tubular cells in the renal collecting duct (CD), its biological actions modulating cardiorenal function in physiological conditions remain unknown. Therefore, the objective of our study was to investigate whether CD-derived human sPRR (HsPRR) expression influences cardiorenal function and examine sex and circadian differences. Thus, we investigated the status of the intrarenal RAS, water and electrolyte balance, renal filtration capacity, and blood pressure (BP) regulation in CD-HsPRR and control (CTL) mice. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag mice with Hoxb7/Cre mice. Renal sPRR expression increased in CD-HsPRR mice, but circulating sPRR and RAS levels were unchanged compared with CTL mice. Only female littermates expressing CD-HsPRR showed 1) increased 24-h BP, 2) an impaired BP response to an acute dose of losartan and attenuated angiotensin II (ANG II)-induced hypertension, 3) reduced angiotensin-converting enzyme activity and ANG II content in the renal cortex, and 4) decreased glomerular filtration rate, with no changes in natriuresis and kaliuresis despite upregulation of the β-subunit of the epithelial Na+ channel in the renal cortex. These cardiorenal alterations were displayed only during the active phase of the day. Taken together, these data suggest that HsPRR could interact with ANG II type 1 receptors mediating sex-specific, ANG II-independent renal dysfunction and a prohypertensive phenotype in a sex-specific manner. NEW & NOTEWORTHY: We successfully generated a humanized mouse model that expresses human sPRR in the collecting duct. Collecting duct-derived human sPRR did not change circulating sPRR and RAS levels but increased daytime BP in female mice while showing an attenuated angiotensin II-dependent pressor response. These findings may aid in elucidating the mechanisms by which women show uncontrolled BP in response to antihypertensive treatments targeting the RAS, improving approaches to reduce uncontrolled BP and chronic kidney disease incidences in women. [ABSTRACT FROM AUTHOR]

Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin–angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes. [ABSTRACT FROM AUTHOR]

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

Renin–angiotensin–aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a serious complication of diabetes, and its progression is influenced by factors like oxidative stress, inflammation, cell death, and fibrosis. Compared to drug treatment, exercise offers a cost-effective and low-risk approach to slowing down DN progression. Through multiple ways and mechanisms, exercise helps to control blood sugar and blood pressure and reduce serum creatinine and albuminuria, thereby alleviating kidney damage. This review explores the beneficial effects of exercise on DN improvement and highlights its potential mechanisms for ameliorating DN. In-depth understanding of the role and mechanism of exercise in improving DN would pave the way for formulating safe and effective exercise programs for the treatment and prevention of DN. [ABSTRACT FROM AUTHOR]

Background/Aim. The renin-angiotensin system (RAS) is linked to the development of atherosclerosis (As), including its initiation and progression. Besides the well-known angiotensin-converting enzyme (ACE), two newer RAS family members are related to vascular remodeling - ACE2 as a homolog of ACE and collectrin [transmembrane protein 27 (TMEM27)] as a homolog of ACE2. Up to now, a limited number of studies have examined the expression of these RAS components in advanced carotid plaque (CP) tissue based on the sex of the patients and plaque phenotypes (PPs). There are two ultrasonographically defined PPs - the hypoechogenic plaque (HoP) and the hyperechogenic plaque (HerP) phenotype. The aim of the study was to investigate whether there was a correlation between the expression of RAS components in the CP and the sex and PPs of patients. Methods. We examined 74 patients with advanced CP who underwent carotid endarterectomy. The intraplaque expression of RAS components was determined with the real-time polymerase chain reaction, using the TaqMan® gene expression assays and Western blot. A two-way ANOVA followed by a post-hoc Tukey test was performed for the statistical analysis of results. Results. No interaction was recorded between the sex of the patients and PPs in influencing the relative expression of ACE and TMEM27 messenger RNA (mRNA) (p > 0.05). In 56.06% of plaque samples, no expression of ACE2 mRNA was detected. Among the plaques where ACE2 mRNA expression was detected, its expression level was higher in females with the HoP phenotype compared to females with the HerP phenotype (p < 0.001). In patients with the HoP phenotype, females had higher expression of ACE2 mRNA than males (p < 0.05). In the male study group, ACE protein levels were significantly lower in the HoP phenotype compared to the HerP phenotype (p < 0.001). Females with the HoP phenotype had significantly higher ACE protein levels than males with the HoP phenotype (p < 0.0001). Conclusion. Our results revealed alterations in the expression levels of ACE and ACE2, at the mRNA and protein levels, in advanced carotid As. These alterations are impacted by sex and PP and may indicate a switch from the balanced RAS/ACE/ACE2 axis in the healthy blood vessel to the unbalanced axis in vascular remodeling due to As. [ABSTRACT FROM AUTHOR]

Objective(s): Pulmonary arterial hypertension (PAH) is a severe and often fatal disease that is associated with oxidative stress and inflammation. Alamandine, a component of the renin-angiotensin system, known for its antioxidative, anti-inflammatory, and antifibrotic effects, has been investigated in this study to determine if it has protective effects against PAH induced by monocrotaline (MCT) and if these effects are associated with oxidative stress, inflammatory factors, and inducible nitric oxide synthase (iNOS). Materials and Methods: Rats were administered MCT (40 mg/kg) on day 0 and then received alamandine (50 mg/kg/day) via mini-osmotic pumps for 21 days starting one day later. Hemodynamic parameters, electrocardiograms, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), inflammatory cytokines (TNF-α, IL-1β, and NF-κB), iNOS, and MrgD receptor expression in lung tissue were evaluated at the end of the 21-day period. The MrgD receptor was quantified through immunofluorescent staining, and the histopathology of lung tissues was evaluated using hematoxylin and eosin staining. Results: The results showed that alamandine treatment significantly improved hemodynamic parameters, oxidative stress markers, inflammatory factors, and electrocardiographic data. Furthermore, treatment with alamandine decreased the levels of iNOS. Additionally, alamandine treatment decreased the expression levels of MrgD receptors in the lung tissue of MCT-induced PAH. Conclusion: In summary, this study indicates that alamandine has protective effects against monocrotaline-induced PAH, and these effects may be attributed to the inhibition of oxidative stress, inflammatory parameters, and iNOS. [ABSTRACT FROM AUTHOR]

Currently, limited data exist regarding the pathological changes occurring during the incubation phase of SARS-CoV-2 infection. We utilized proteomic analysis to explore changes in the circulatory host response in individuals with SARS-CoV-2 infection before the onset of symptoms. Participants were individuals from a randomized clinical trial of prophylaxis for COVID-19 in a workers' dormitory. Proteomic signatures of blood samples collected within 7 days before symptom onset (incubation group) were compared with those collected >21 days (non-incubation group) to derive candidate biomarkers of incubation. Candidate biomarkers were assessed by comparing levels in the incubation group with both infected individuals (positive controls) and non-infected individuals (negative controls). The study included men (mean age 34.2 years and standard deviation 7.1) who were divided into three groups: an incubation group consisting of 44 men, and two control groups—positive (n = 56) and negative (n = 67) controls. Through proteomic analysis, we identified 49 proteins that, upon pathway analyses, indicated an upregulation of the renin-angiotensin and innate immune systems during the virus incubation period. Biomarker analyses revealed increased concentrations of plasma angiotensin II (mean 731 vs. 139 pg/mL), angiotensin (1–7) (302 vs. 9 pg/mL), CXCL10 (423 vs. 85 pg/mL), CXCL11 (82.7 vs. 32.1 pg/mL), interferon-gamma (0.49 vs. 0.20 pg/mL), legumain (914 vs. 743 pg/mL), galectin-9 (1443 vs. 836 pg/mL), and tumour necrosis factor (20.3 vs. 17.0 pg/mL) during virus incubation compared with non-infected controls (all p < 0.05). Plasma angiotensin (1–7) exhibited a significant increase before the onset of symptoms when compared with uninfected controls (area under the curve 0.99, sensitivity 0.97, and specificity 0.99). Angiotensin (1–7) could play a crucial role in the progression of symptomatic COVID-19 infection, and its assessment could help identify individuals who would benefit from enhanced monitoring and early antiviral intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: The renin-angiotensin system plays a key role in the occurrence and development of hypertension, in which angiotensin (1-7) has antihypertensive effect and reversely regulates the adverse effects of angiotensin II. Exercise rehabilitation therapy is an important non-pharmaceutical means to prevent and treat hypertension; however, whether angiotensin (1-7) and exercise have a synergistic effect is not yet clear. OBJECTIVE: To explore the effect of angiotensin (1-7) supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension and to investigate the possible mechanism of angiotensin (1-7) and its receptor signal axis. METHODS: Sixty male Sprague-Dawley rats were selected, of which 12 rats were randomly selected as normotensive group and the remaining 48 rats were used to make animal models of renal hypertension using two-kidney one-clip method and were then randomly divided into hypertension control group, hypertension exercise group, angiotensin (1-7) group and combined treatment group. One week after successful modeling, different interventions were given (for a period of 6 weeks) as follows: the hypertension exercise group was subjected to a running training on an electric treadmill, the angiotensin (1- 7) group was perfused with angiotensin (1-7) by implanting Alzet microosmotic pump subcutaneously on the back of the rats, and the combined treatment group was perfused with angiotensin (1-7) after running training, while the normotensive group and hypertension control group were caged quietly. At 48 hours after the last training session, the tail artery blood pressure was measured with a non-invasive sphygmomanometer; the heart structure and function were detected by echocardiography; the left ventricular myocardium was taken for histopathological observation by hematoxylin-eosin and Masson staining, and the cardiomyocyte cross-sectional area and collagen volume fraction were obtained by image analysis software as markers of myocardial hypertrophy and fibrosis, respectively; the content of angiotensin (1-7) in the heart was detected by high performance liquid chromatography; the mRNA expression of cardiac embryonic genes, atrial natriuretic peptide and β-myosin heavy chain, was detected by real-time fluorescence quantitative PCR; and the protein expression of cardiac Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was measured by western blot assay. RESULTS AND CONCLUSION: Compared with the normotensive group, blood pressure increased (P < 0.05), cardiac function had no significant changes (P > 0.05), cardiomyocyte cross-sectional area and collagen volume fraction increased (P < 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was upregulated (P < 0.05), angiotensin (1-7) content and protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was downregulated (P < 0.05) in the hypertension control group. Compared with the hypertension control group, blood pressure decreased (P < 0.05), cardiac function improved (P < 0.05), collagen volume fraction decreased (P < 0.05), cardiomyocyte cross-sectional area and angiotensin (1-7) content showed no significant changes (P > 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated (P < 0.05), and the protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was upregulated (P < 0.05) in the hypertension exercise group; except for an increase in myocardial angiotensin (1-7) content (P < 0.05), other parameters had no statistical significance (P > 0.05) in the hypertension angiotensin (1-7) group. Compared with the hypertension exercise group, blood pressure decreased (P < 0.05), cardiomyocyte cross-sectional area and cardiac function had no significant changes (P > 0.05), collagen volume fraction decreased (P < 0.05), angiotensin (1-7) content increased (P < 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated (P < 0.05), and the protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was upregulated (P < 0.05) in the combined treatment group. To conclude, supplementation of angiotensin (1-7) alone cannot improve cardiac remodeling in rats with renal hypertension, but it can enhance the efficacy of exercise. The mechanism is related to the improvement of angiotensin (1-7) receptor deficiency and restoration of its signaling pathway function. [ABSTRACT FROM AUTHOR]

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter‐regulatory or non‐canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre‐clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type‐2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases. [ABSTRACT FROM AUTHOR]

Aim: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real‐world practice remains unclear. Materials and Methods: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end‐stage kidney disease). Results: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow‐up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin‐angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (β = −0.609, p =.039; β = −2.298, p <.001; β = −0.936, p =.048; β = −0.079, p <.001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p <.001). Conclusions: The concomitant use of renin‐angiotensin system inhibitors and diuretics, higher urine protein levels and pre‐treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes. [ABSTRACT FROM AUTHOR]

The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin prophylaxis. One hour prior to hypobaric hypoxia exposure, male SD rats were orally supplemented with quercetin (50 mg/kg BW) and acetazolamide (50 mg/kg BW) and exposed them to 25,000 ft. (7,620 m) in a simulated environmental chamber for 12 h at 25 ± 2 °C. Different biochemical parameters like renin activity, aldosterone, angiotensin I, ACE 2 were determined in plasma. As a conventional response to low oxygen conditions, oxidative stress parameters (ROS and MDA) were elevated along with suppressed antioxidant system (GPx and catalase) in plasma of rats. Quercetin prophylaxis significantly down regulated the hypoxia induced oxidative stress by reducing plasma ROS & MDA levels with efficient enhancement of antioxidants (GPx and Catalase). Further, hypoxia mediated regulation of renin and ACE 2 proves the outstanding efficacy of quercetin in repudiating altercations in RAAS cascade due to hypobaric hypoxia. Furthermore, differential protein expression of HIF-1α, NFκB, IL-18 and endothelin-1 analyzed by western blotting approves the biochemical outcomes and showed that quercetin significantly aids in the reduction of inflammation under hypoxia. Studies conducted with Surface Plasmon Resonance demonstrated a binding among quercetin and ACE 2 that indicates that this flavonoid might regulate RAAS pathway via ACE 2. Henceforth, the study promotes the prophylaxis of quercetin for the better adaptability under hypobaric hypoxic conditions via modulating the RAAS pathway. [ABSTRACT FROM AUTHOR]

The identification of pathological links among metabolic disorders, kidney ailments, and cardiovascular conditions has given rise to the concept of cardiovascular–kidney–metabolic (CKM) syndrome. Emerging prenatal risk factors seem to increase the likelihood of CKM syndrome across an individual's lifespan. The renin–angiotensin system (RAS) plays a crucial role in maternal–fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review consolidates current preclinical evidence detailing how dysregulation of the RAS during pregnancy and lactation leads to CKM characteristics in offspring, elucidating the underlying mechanisms. The multi-organ effects of RAS, influencing fetal programming and triggering CKM traits in offspring, suggest it as a promising reprogramming strategy. Additionally, we present an overview of interventions targeting the RAS to prevent CKM traits. This comprehensive review of the potential role of the RAS in the early-life programming of CKM syndrome aims to expedite the clinical translation process, ultimately enhancing outcomes in cardiovascular–kidney–metabolic health. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age‐matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE‐1 and ACE‐2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang‐II, Ang‐III and Ang‐(1–7)) levels were measured by ELISA. ACE‐1 protein level and enzyme activity, and Ang‐II and Ang‐III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE‐1 and Ang‐II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE‐2 level was elevated in frontal white matter in vascular dementia. Ang‐(1–7) level was elevated across all dementia groups compared to age‐matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE‐1 protein was reduced and ACE‐2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease. [ABSTRACT FROM AUTHOR]

Background: Pregnancy is characterized by profound circulatory changes and compensatory adjustments in the renin-angiotensin-aldosterone system (RAAS). Differences in regulatory response may antedate or accompany vascular complicated pregnancy. We performed a systematic review and meta-analysis to delineate the trajectory of active plasma renin concentration (APRC) in healthy pregnancy and compare this to complicated pregnancy. Methods: We performed a systematic review and meta-analysis on APRC during normotensive and hypertensive pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. We included only studies reporting measurements during pregnancy together with a nonpregnant reference group measurement. Risk of bias was assessed with QUIPS. Ratio of the mean (ROM) and 95% confidence intervals (CI) of APRC values between pregnant and nonpregnant women were estimated for predefined intervals of gestational age using a random-effects model. Meta-regression was used to analyze APRC over time. Results: In total, we included 18 studies. As compared to nonpregnant, APRC significantly increased as early as the first weeks of healthy pregnancy and stayed increased throughout the whole pregnancy (ROM 2.77; 95% CI 2.26–3.39). APRC in hypertensive complicated pregnancy was not significantly different from nonpregnancy (ROM 1.32; 95% CI 0.97–1.80). Conclusion: Healthy pregnancy is accompanied by a profound rise in APRC in the first trimester that is maintained until term. In hypertensive complicated pregnancy, this increase in APRC is not observed. [ABSTRACT FROM AUTHOR]

The article discusses the underutilization of ambulatory blood pressure monitoring (ABPM) in patients with childhood-onset systemic lupus erythematosus (SLE). ABPM has been shown to have advantages over clinic blood pressure measurements, but its use in patients with childhood-onset SLE is low, despite the known cardiovascular risk associated with the condition. The article presents data from a nationally representative sample and a single-center cohort, highlighting the discrepancy between the prevalence of potential ABPM indications and the actual utilization of ABPM in patients with childhood-onset SLE. The authors emphasize the need for multidisciplinary approaches to improve cardiovascular outcomes in this population and call for further research on the optimal timing and frequency of ABPM. They also highlight the importance of understanding barriers to the uptake of ABPM in order to effectively improve cardiovascular health in this population. [Extracted from the article]

Although diuretics play an important role in triple‐whammy acute kidney injury (AKI), it is unclear whether the type of diuretic influences the risk of triple‐whammy AKI. The aim of this study was to evaluate whether vasopressin receptor antagonists affect triple‐whammy AKI. This cross‐sectional study used disproportionality analysis of VigiBase data to assess the risk of AKI with various diuretics. Although multiple logistic regression analysis showed that aldosterone antagonists (odds ratio [OR] 2.19, 95% CI 2.01–2.37), loop diuretics (OR 4.40, 95% CI 4.07–4.76) and thiazide diuretics (OR 1.98, 95% CI 1.83–2.15) increased the risk of AKI in patients who received non‐steroidal anti‐inflammatory drugs (NSAIDs) and renin‐angiotensin system inhibitors (RASi), vasopressin receptor antagonists did not increase the risk of AKI in those patients. Vasopressin receptor antagonists might not influence the development of triple‐whammy AKI. [ABSTRACT FROM AUTHOR]

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance. [ABSTRACT FROM AUTHOR]

Clinical outcomes after catheter ablation in patients with reduced left ventricular (LV) ejection fraction (EF) and atrial fibrillation (AF) remain unclear. This study aimed to explore the clinical outcomes of patients with arrhythmia-induced cardiomyopathy (AIC) and the influence of pharmacological treatment on clinical outcomes in patients with AIC after the procedure. Ninety-six patients with AF with a reduced LVEF (LVEF < 50%, 66.7 ± 10.9 years; 72 males) underwent AF ablation. AIC was defined as patients whose LVEF recovered ≥ 50% after catheter ablation (n = 67) and patients whose LVEF remained reduced were defined as non-AIC (n = 29). During a median follow-up of 25 (13–40) months, Kaplan–Meier analysis demonstrated that patients with AIC were associated with less frequent cardiovascular death (p = 0.025) and hospitalization for worsening heart failure (p < 0.001) than those without AIC. Freedom from AF recurrence was similar between the two groups (p = 0.47). In multivariate analysis, the LV end-diastolic diameter (p = 0.0002) and the CHA2DS2-VASc scores (p = 0.0062) were independent predictors of AIC. Among the 67 patients with AIC, no significant differences in baseline characteristics, except for LV chamber size and cryoballoon use, were observed between patients with AIC with (n = 31) and without renin–angiotensin system (RAS) inhibitors (n = 36). In the Kaplan–Meier analysis, cardiovascular death, hospitalization for worsening heart failure, and AF recurrence after catheter ablation did not differ between patients treated with and without RAS inhibitors (all p > 0.05). Catheter ablation in patients with AIC due to AF is associated with a good post-procedural prognosis. IRB information The study was approved by the Research Ethics Committee of the University of Fukui (No. 20220151) and clinical trial registration (UMIN000050391). [ABSTRACT FROM AUTHOR]

During the early stages of the development of the living multiorgan systems, genome modifications other than sequence variation occur that guide cell differentiation and organogenesis. These modifications are known to operate as a fetal programming code during this period, and recent research indicates that there are some tissue-specific codes in organogenesis whose effects may persist after birth until adulthood. Consequently, the events that disrupt the pre-established epigenetic pattern could induce shifts in organ physiology, with implications on health from birth or later in adult life. Chronic kidney disease (CKD) is one of the main causes of mortality worldwide; its etiology is multifactorial, but diabetes, obesity, and hypertension are the main causes of CKD in adults, although there are other risk factors that are mainly associated with an individual's lifestyle. Recent studies suggest that fetal reprogramming in the developing kidney could be implicated in the susceptibility to kidney disease in both childhood and adulthood. Some epigenetic modifications, such as genome methylation status, dysregulation of miRNA, and histone coding alterations in genes related to the regulation of the renin-angiotensin axis, a common denominator in CKD, may have originated during fetal development. This review focuses on epigenetic changes during nephrogenesis and their repercussions on kidney health and disease. In addition, the focus is on the influence of environmental factors during pregnancy, such as maternal metabolic diseases and dietary and metabolic conditions, as well as some sex differences in fetal kidney reprogramming during which dysregulation of the renin-angiotensin system is involved. [ABSTRACT FROM AUTHOR]