Renin-angiotensin Research Articles

SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

Organ-protective effects of the alternative renin-angiotensin system and prospects for therapeutic treatment. Review

The article is devoted to review the data regarding the identification of biochemical and functional features of the components of the renin‑angiotensin system using the tools of bibliometric analysis of scientific literature. A modern interpretation by the dividing of the multifunctional complex into two systems, namely the classical renin‑angiotensin system and alternative renin‑angiotensin system, in accordance with the definition of biological effects, is given. The enzymatic cascade involved in the production and metabolism of peptides in both classical and non‑classical pathways of renin‑angiotensin systems is shown from the point of view of the evolution of scientific concepts. The triggering role of components of the classical renin‑angiotensin system in pathophysiological processes with transformation into cardiovascular diseases and metabolic dysfunction has been proven. The history of the creation of pharmacological drugs for the correction of the classic renin‑angiotensin system is presented. In view of the achievement of recent years, the revision of the alternative renin‑angiotensin system is emphasized due to the discovery of the counter‑regulatory action of the angiotensin‑converting enzyme 2, angiotensin‑(1—7), the Mas receptor in relation to their correction of metabolic processes, regulation of blood pressure, and the presence of anti‑fibrotic, anti‑inflammatory and antioxidant properties. The positive effect of the components of the non‑classical renin‑angiotensin system on the protection of the cardiovascular system and kidney is presented based on the results of experimental studies on animals. Pharmacokinetic and pharmacodynamics characteristics of recombinant angiotensin‑converting enzyme 2 in experiments on healthy volunteers are highlighted. The potential protective effects of angiotensin‑converting enzyme 2 and angiotensin‑(1—7) concerning cardiometabolic risk are presented. The available data indicate the need for further comprehensive scientific investigations of the components of alternative renin‑angiotensin system to create a new class of pharmacological agents with their implementation in medical practice.

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

Polycystic Ovarian Syndrome: Exploring Hypertension and Cardiometabolic Implications.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, with significant implications for cardiometabolic health. This review focuses on the relationship between PCOS and hypertension (HTN), an area that remains underexplored despite growing evidence of its importance. PCOS is characterized by hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovarian morphology (PCOM), all of which contribute to a complex metabolic profile that includes insulin resistance (IR), obesity, and dyslipidemia. These factors collectively exacerbate the risk of HTN. Emerging research suggests HA in PCOS may directly influence the renin-angiotensin system (RAS), increasing blood pressure by promoting sodium retention and vascular tone. Additionally, IR, prevalent in both lean and obese women with PCOS, further contributes to HTN by enhancing sympathetic nervous system activity and impairing endothelial function. Despite these associations, the direct link between PCOS and HTN has not been definitively established, warranting further investigation. This review synthesizes current knowledge on the etiology of PCOS and its metabolic consequences, highlighting the need for targeted research to clarify the mechanisms linking PCOS with HTN. Understanding these pathways is crucial for improving the management of PCOS and reducing cardiovascular risks in affected women. By addressing these gaps, this review underscores the importance of considering HTN as a significant comorbidity in PCOS and calls for more comprehensive studies to guide clinical practice.

7094 Post Unilateral Adrenalectomy Hyporeninemic Hypoaldosteronism: Requiring Long Term Fludrocortisone In Managing Hyperkalemia And Renal Dysfunction

Abstract Disclosure: R. Rani: None. K. Bidani: None. R. Roy: None. Adrenalectomy, seen as a potentially curative measure for unilateral aldosterone-producing adenoma (APA), targets both biochemical and clinical resolution. However, postoperative challenges may arise, including acute renal failure and hyperkalemia, due to inadequate aldosterone secretion, a consequence of prolonged suppression of the renin-angiotensin-aldosterone system (RAAS) on the contralateral side. Our case underscores the postoperative challenge of isolated aldosterone deficiency leading to renal function deterioration and hyperkalemia, necessitating fludrocortisone therapy. We are presenting case of 71-year-old male with a history of uncontrolled hypertension for over 30 years with hypokalemia (taking KCL 20mEq daily). Initial laboratory findings revealed elevated aldosterone levels 79ng/dL and an aldosterone-to-renin ratio (ARR)&amp;gt; 20, K- 3.2mmol/L, creatinine 1.32mg/dl, Na-145 mmol/L with normal cortisol and plasma metanephrines levels. CT abdomen disclosed a 21 x 18 mm right adrenal adenoma, with subsequent confirmation of lateralization through Adrenal vein sampling. The patient underwent right adrenalectomy. Two weeks post-surgery, he presented to the emergency department with symptoms of fatigue and weakness. Laboratory results indicated hyperkalemia (K- 6.5 mmol/L) and elevated creatinine (3.52mg/dl) with undetectable aldosterone and renin levels. Urinalysis and CT abdomen ruled out other causes of acute renal injury. Initial management included intravenous fluids and Potassium supplementation. However, due to persistent hypokalemia, the patient was initiated on fludrocortisone (0.1 mcg daily). Subsequent follow-up demonstrated improvement in renal function and potassium levels, however, his aldosterone and renin levels remain undetectable. Hyperkalemia incidence post-adrenalectomy in primary aldosteronism (PA) ranges from 6.3% to 29.1%. Notably, older age and preexisting impaired renal function, particularly in cases with prolonged hypertension are identified as potential risk factors for postoperative hyperkalemia and renal failure. Understanding the potential for a further decline in the glomerular filtration rate (GFR) post-surgery becomes crucial. This decline might manifest as a transient or permanent issue, necessitating prolonged fludrocortisone treatment. This case highlights the importance of tailored preoperative assessment and postoperative management to mitigate complications in high-risk populations. Presentation: 6/1/2024

New insights into prostate Cancer from the renin-angiotensin-aldosterone system.

Prostate cancer is among the most common malignancies found in men, with multifactorial changes occurring altogether to disrupt the pathophysiology of this gland. The Renin-Angiotensin-Aldosterone System (RAAS) is an extensively studied pathway that has newly attributed fundamental roles in cancer biology that impact cell growth, migration, metastasis, and death. These processes are significantly influenced by various components of the RAAS, including prorenin, AT1R, AT2R, and Ang 1–7/Mas receptors. Although the pathophysiology of prostate cancer is complex, targeting the RAAS shows promise as a therapeutic approach. RAAS dysregulation is evident in prostate cancer, and treatments traditionally used for cardiovascular diseases are being explored for cancer therapy. The RAAS pathway has significant effects on the formation of new blood vessels (angiogenesis), the spread of cancer cells to other parts of the body (metastasis), and cell proliferation. In this pathway, angiotensin II and its receptors have crucial functions. Angiotensin II stimulates angiogenesis and cell proliferation through the AT1R, whereas the AT2R has the opposite effect by inhibiting cell growth. Additional pathways involving ACE2/Ang 1–7/Mas also provide potential targets for therapeutic intervention, mitigating the impact of the traditional ACE/Angiotensin II/AT1R pathway. The components of the RAAS influence multiple signalling pathways, such as Androgen Receptor (AR), NF-κB, and PI3K/AKT/mTOR, which enhances our understanding of how it contributes to the progression of prostate cancer. This also provides new possibilities for therapeutic interventions.

Prescribing patterns in older people with advanced chronic kidney disease towards the end of life

ABSTRACT Background Advancing age and chronic kidney disease (CKD) are risk factors for polypharmacy. Polypharmacy is associated with negative healthcare outcomes. Deprescribing, the systematic rationalization of potentially inappropriate medications, is a proposed way of addressing polypharmacy. The aim of this study was to describe longitudinal prescribing patterns of oral medications in a cohort of older people with advanced CKD in their last years of life. Methods The European QUALity (EQUAL) study is a European, prospective cohort study of people ≥65 years with an incident estimated glomerular filtration rate (eGFR) of ≤20 mL/min/1.73 m2. We analysed a decedent subcohort, using generalized additive models to explore trends in the number and types of prescribed oral medications over the years preceding death. Results Data from 563 participants were analysed (comprising 2793 study visits) with a median follow-up time of 2.2 years (interquartile range 1.1–3.8) pre-death. Participants’ numbers of prescribed oral medications increased steadily over the years approaching death—7.3 (95% confidence interval 6.9–7.7) 5 years pre-death and 8.7 (95% confidence interval 8.4–9.0) at death. Over the years pre-death, the proportion of people prescribed (i) proton-pump inhibitors and opiates increased and (ii) statins, calcium-channel blockers and renin–angiotensin–aldosterone system inhibitors decreased, whilst (iii) beta-blockers, diuretics and gabapentinoids remained stable. At their final visits pre-death 14.6% and 5.1% were prescribed opiates and gabapentinoids, respectively. Conclusion Elderly people with advanced CKD experienced persistent and increasing levels of polypharmacy as they approached the end of life. There was evidence of cessation of certain classes of medications, but at a population level this was outweighed by new prescriptions. This work highlights the potential for improved medication review in this setting to reduce the risks associated with polypharmacy. Future work should focus at the individual patient–clinician level to better understand the decision-making process underlying the observed prescribing patterns.

Prescription of quadruple therapy in heart failure with reduced ejection fraction during hospitalization

BackgroundHospitalization of patients with heart failure makes it possible to optimize drug therapy, considerably improving the prognosis of this serious condition.MethodsWe conducted a retrospective descriptive study of patients with reduced left ventricular ejection fraction (≤ 40%) in the Cardiology Department of a community hospital center in France to measure the prescription rate of heart failure medications in hospitalized patients with reduced ejection fraction heart failure and identify their limiting factors. The primary endpoint was the prescription on the discharge prescription of the following four drug classes: beta-blockers, renin–angiotensin–aldosterone system blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter inhibitors.ResultsFrom September 1, 2022, to March 31, 2023, 73 patients were included in the study. About one-third of patients were discharged with the recommended four drug classes. Those discharged with all 4 drug classes were younger and had preserved renal function.ConclusionsThe low rate of prescription of heart failure medications after hospitalization is a reminder of the need to develop a specialized follow-up structure to optimize the drug treatment of reduced ejection fraction heart failure, even in the most fragile patients.

The Increasing Problem of Resistant Hypertension: We'll Manage till Help Comes!

Arterial hypertension remains the major cardiovascular risk worldwide. It is estimated that under 50 years of age one in every three adults is hypertensive while beyond the age of 50 the prevalence is almost 50% globally. The latest World Health Organization (WHO) Global Report on Hypertension indicated that the global number of hypertensive patients almost doubled in the last three decades, with related increasing deaths, disability, and costs annually. Because of this global increase, early diagnosis and timely treatment is of great importance. However, based on the WHO Global Report, it is estimated that up to 46% of individuals were never diagnosed. Of those diagnosed, less than 50% were on treatment, with nearly half among these at target according to the current guidelines. It is also important to note that an increasing number of hypertensive patients, despite the use of three or more drugs, still do not achieve a blood pressure normalization, thus defining the clinical scenario of resistant hypertension (RH). This condition is associated to a higher risk of hypertension-mediated organ damage and hospitalization due to acute cardiovascular events. Current guidelines recommend a triple combination therapy (renin angiotensin system blocking agent + a thiazide or thiazide-like diuretic + a dihydropyridinic calcium-channel blocker) to all patients with RH. Beta-blockers and mineralocorticoid receptor antagonists, alone or in combination, should be also considered based on concomitant conditions and potential contraindications. Finally, the renal denervation is also proposed in patients with preserved kidney function that remain hypertensive despite the use of maximum tolerated medical treatment. However, the failure of this procedure in the long term and the contraindication in patients with kidney failure is a strong call for a new therapeutic approach. In the present review, we will discuss the pharmacological novelties to come for the management of hypertension and RH in the next future.

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

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

Sacubitril/valsartan reduces proteinuria depending on blood pressure in patients with stage 4-5 chronic kidney disease.

Blood pressure (BP) control is an important factor in the management of chronic kidney disease (CKD). Several studies have shown that BP in many patients with CKD remained uncontrolled even with multiple medications. Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has been newly approved for treating hypertension in Japan. However, the renoprotective effects remain unclear, particularly in patients with advanced CKD. Here, we investigated the effects on proteinuria of this ARNI in patients with stage 4-5 CKD. We retrospectively collected data from outpatients with stage 4-5 CKD who started ARNI from January until December 2023. The primary outcome was the change in urine protein creatinine ratio (UPCR) at 6months after ARNI initiation. Secondary outcomes were systolic and diastolic BP, estimated glomerular filtration rate (eGFR), serum potassium, and serum uric acid (UA). We analyzed factors associated with 50% UPCR reduction by multivariate analysis. In total, 47 patients were analyzed. ARNI reduced UPCR from 2.14g/gCr (interquartile range; 1.09-2.91) to 1.05g/gCr (0.42-1.95; p < 0.001). Systolic BP fell from 150.0mmHg (139.5-160.0) to 134.0mmHg (124.5-140.0; p < 0.001). No significant changes in eGFR, serum potassium, and serum uric acid were observed, except for a slight decrease in eGFR among patients with conversion from a renin-angiotensin system inhibitor to ARNI. In multivariate regression analysis, higher systolic BP (per 10-mmHg increase) was significantly associated with reduced proteinuria (odds ratio 2.51, 95% confidence interval 1.35-4.66; p = 0.004). ARNI reduced proteinuria in patients with stage 4-5 CKD, particularly for those with uncontrolled hypertension.

Extraperitoneal Robot-Assisted Radical Prostatectomy with the Hugo™ RAS System: Initial Experience at a High-Volume Robotic Centre.

Background: The Hugo™ Robotic-Assisted Surgery (Hugo™ RAS) system represents a novel advancement in robotic surgical technology. Despite this, there remains a scarcity of data regarding extraperitoneal robot-assisted radical prostatectomy (eRARP) using this system. Methods: We conducted a prospective study at Ospedale Regionale "F. Miulli" from June 2023 to January 2024, enrolling consecutive patients diagnosed with prostate cancer (PCa) undergoing eRARP ± lymph node dissection. All procedures employed a modular four-arm setup performed by two young surgeons with limited prior robotic surgery experience. This study aims to evaluate the safety and feasibility of eRARP using the Hugo™ RAS system, reporting comprehensive preoperative, intraoperative, and postoperative outcomes in the largest reported cohort to date. Results: A total of 50 cases were analyzed, with a mean patient age of 65.76 (±5.57) years. The median operative time was 275 min (Q1-Q3 150-345), and the console time was 240 min (Q1-Q3 150-300). The docking time averaged 10 min (Q1-Q3 6-20). There were no intraoperative complications recorded. Two major complications occurred within the first 90 days. At the 3-month mark, 36 patients (72%) achieved undetectable PSA levels (<0.1 ng/mL). Social continence was achieved by 66% of patients, while 40% maintained erectile function. Conclusions: eRARP utilizing the Hugo™ RAS system demonstrated effectiveness and safety in our study cohort. However, more extensive studies with larger cohorts and longer follow-up periods are necessary to thoroughly evaluate long-term outcomes.

3D monitors improve performance on the HUGO™ RAS system: a randomised trial.

Robot-assisted surgery is used worldwide, allowing surgeons to perform complex surgeries with increased precision and flexibility. It offers technical benefits compared to traditional laparoscopic surgery due to its utilization of both 3D vision and articulated instruments. The objective was to investigate the isolated effect of 3D- versus 2D monitors when working with articulated instruments in robot-assisted surgery. Surgical novices (medical students, n = 31) were randomized to simulation-based training with either the 3D vision switched on or off. Both groups completed each of the four exercises six times over two sessions on the Medtronic Hugo™ RAS system simulator. The outcome was the simulator performance parameters and a visual discomfort questionnaire. For the efficiency parameters, we found that both groups improved over time (p < 0.001) and that the intervention group (3D) consistently outperformed the control (2D) group (p < 0.001). On the other hand, we didn't find any significant difference in the error metrics, such as drops (p-values between 0.07 and 0.57) and instrument collisions (p-values between 0.09 and 0.26). Regarding Visual Discomfort, it was significantly more difficult for the 3D group to focus (p = 0.001). 3D monitors for an open robotic console improve efficiency and speed compared to 2D monitors in a simulated setting when working with articulated instruments.

SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model.

COVID-19 increases the risk for acute ischemic stroke, yet the molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that the SARS-CoV-2 spike protein exacerbates stroke and cerebrovascular complications by increasing coagulation and decreasing fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS). A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of SARS-CoV-2 spike protein injection. hACE2 mice were treated with Losartan, an angiotensin receptor (AT1R) blocker, immediately after spike protein injection. Cerebral blood flow and infarct size were compared between groups. Vascular-contributes to cognitive impairments and dementia was assessed using a Novel object recognition test. Tissue factor-III and plasminogen activator inhibitor-1 were measured using immunoblotting to assess coagulation and fibrinolysis. Human brain microvascular endothelial cells (HBMEC) were exposed to hypoxia with/without SARS-CoV-2 spike protein to mimic ischemic conditions and assessed for inflammation, RAAS balance, coagulation, and fibrinolysis. Our results showed that the SARS-CoV-2 spike protein caused an imbalance in the RAAS that increased the inflammatory signal and decreased the RAAS protective arm. SARS-CoV-2 spike protein increased coagulation and decreased fibrinolysis when coincident with ischemic insult, which was accompanied by a decrease in cerebral blood flow, an increase in neuronal death, and a decline in cognitive function. Losartan treatment restored RAAS balance and reduced spike protein-induced effects. SARS-CoV-2 spike protein exacerbates inflammation and hypercoagulation, leading to increased neurovascular damage and cognitive dysfunction. However, the AT1R blocker, Losartan, restored the RAAS balance and reduced COVID-19-induced thromboembolic cerebrovascular complications.

A-067 Simultaneous Measurement of Aldosterone and Plasma Renin Activity in Human Serum Using Liquid Chromatography Coupled to Tandem Mass Spectrometry for Clinical Research

Abstract Background The combination of primary aldosteronism (PA) and alterations in plasma renin activity (PRA) is a leading cause of secondary hypertension. An accurate measurement of Renin Angiotensin-Aldosterone System (RAAS) pathway improves the recognition of symptoms related to stroke, coronary disease, heart failure and metabolic syndrome. Methods Previously, surrogate matrices have been used when demonstrating the analytical performance of LC-MS/MS clinical research methods for the measurement of aldosterone and angiotensin I. Here, we have developed an analytically sensitive and reliable analytical strategy for simultaneous measurement of Aldosterone and Angiotensin I in human matrices. In-house calibrators and quality control samples were prepared, containing varying ranges of both aldosterone (20-2000pg/mL; 55-5548pmol/L) and angiotensin 1 (0.6-240ng/mL; 0.46-185nmol/L). The samples were extracted using the Oasis™ MAX 96-well µElution plate and then separated through the ACQUITY™ UPLC™ I-Class FL System using a XBridge™ Premier Peptide BEH™ C18 Column, over a run time of 3 minutes. Samples were then injected to Xevo™ TQ Absolute Mass Spectrometer, using both positive and negative acquisition modes. The downstream LC-MS/MS data analysis was performed using MassLynx™ MS Software. The analytical performance was demonstrated by extracting and quantifying two replicates of samples on two occasions per day over five separate days. Additionally, the stability of aldosterone and angiotensin I over the period of incubation (3-5hr) was evaluated, which is necessary when investigating the plasma renin activity in human Serum/Plasma samples. Results High reproducibility and repeatability were both determined, indicating total precision and repeatability (&amp;lt;15%CV) for both analytes and no significant changes were found in Aldosterone and Angiotensin I concentrations over 3-5hr of incubation. No significant system carryover (&amp;lt;10% of the lowest calibrator) from high concentration samples into subsequent blank injections was observed. In addition, calibration lines in human serum/plasma were linear, with coefficient of determinations (r2) &amp;gt;0.992 for all analyses at different incubation times. The analytical sensitivity of the clinical research method allows for precise quantification at 55 pmol/L for aldosterone and 0.46 nmol/L/hr for angiotensin I, with both analytes providing S/N (PtP) ≥10:1 and %RSD of &amp;lt;15% at these concentrations. Conclusions An analytically sensitive and selective clinical research method has been developed for the analysis of aldosterone and angiotensin I, using the Xevo TQ Absolute Mass Spectrometer. The Xevo TQ Absolute Mass Spectrometer enables the simultaneous analysis of physiologically low levels of aldosterone and plasma renin activity in human samples, (20pg/mL; 55pmol/L), (0.6ng/mL; 0.46nmol/h/L). A single test that improves instrument utilization, reduces cost, and allows the user to expand their existing test menu on the same platform has been established.

Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic, but Not Diastolic, Function through β-AR Responsiveness in a Rat Model of Type 2 Diabetes

Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin–angiotensin–aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through β-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure–volume loop analysis. β-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. β1-/β2-AR-mediated responsiveness was partially restored in treated animals. β3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness.

Management of acute kidney disease in type 2 diabetes: the potential role of GLP-1 RAs and SGLT2-Is.

Acute kidney disease (AKD) is defined as subacute damage and/or loss of kidney function occurring 7 to 90days after acute kidney injury (AKI), and bearing a high risk of progression to chronic kidney disease. Current management of AKD is non-specific and includes prevention of repeated AKI, early and regular follow-up by a nephrologist, resumption and dose adjustment of statins and renin-angiotensin system inhibitors, optimization of blood pressure control, nutrition management, and nephrotoxin avoidance. Recently, SGLT2i and GLP1- RAs have emerged as potential therapeutic tools preventing the transition from acute to chronic kidney disease due to their efficacy in preserving renal function.

Neuritogenesis and protective effects activated by Angiotensin 1–7 in astrocytes-neuron interaction

The renin angiotensin system (RAS) has been studied for its effects on various neurological disorders. The identification of functional receptors for Ang-(1–7) and Ang II peptides in astrocytes highlights the physiological modulation and the important role of these cells in the central nervous system. The present study aims to understand the role of RAS peptides, particularly Ang-(1–7) and Ang II, in the secretion of trophic factors by astrocytes and their effects on hippocampal neurons. We used primary cultures of astrocytes and neurons from the hippocampus of either sex neonate of Wistar strain rats. In the present study, we demonstrated that the treatment of astrocytes with Ang-(1–7) acts on the modulation of these cells, inducing reactive astrogliosis, identified through the increase in the expression of GFAP. Furthermore, we obtained a conditioned medium from astrocytes treated with Ang-(1–7), which in addition to promoting the secretion of neurotrophic factors essential for neuronal-glial interactions that are fundamental for neuritogenesis and neuronal survival, showed a neuroprotective effect against glutamatergic excitotoxicity. In turn, Ang II does not exhibit the same effects on astrocyte modulation, exacerbating deleterious effects on brain RAS. Neuron-astrocyte interactions have been shown to be an integral part of the central effects mediated by RAS, and this study has significantly contributed to the understanding of the biochemical mechanisms involved in the functioning of this system.

Genetically conditioned interaction among microRNA-155, alpha-klotho, and intra-renal RAS in male rats: Link to CKD progression.

Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit.

Equal Treatment, Unequal Outcomes? Debunking the Racial Disparity in Renin Angiotensin Aldosterone System Inhibitor Associated Reduction in Heart Failure Hospitalizations

BackgroundRenin angiotensin aldosterone system inhibitors (RAASi) are a mainstay treatment in patients with heart failure with reduced ejection fraction (HFrEF) in part to prevent hospitalizations. However, whether RAAS inhibitors reduce the risk of hospitalization in Black patients is not entirely clear because enrollment of Black patients in previous clinical trials was low, and a previous meta-analysis showed a significant racial disparity: reduction in hospitalizations with an RAAS inhibitor in White patients but not Black patients. Previous studies relied on the use of self-identified race instead of genomic ancestry. Therefore, this study aimed to investigate the role of self-identified race and genomic ancestry in the racial disparity in RAAS inhibitor associated reductions in HFrEF hospitalizations. MethodsThe primary outcome was time to first heart failure hospitalization. A (de-identified) heart failure patient registry and data from the GUIDE-IT multi-center randomized control trial were analyzed with Cox proportional hazards models un/adjusted for clinical risk factors, death as a competing risk, and time-varying RAAS inhibitor exposure. The proportion of Yoruba African ancestry was quantified.. Analysis of self – identified race were performed in both the registry and GUIDE-IT. Analysis of genomic ancestry was only performed in the registry since this information was not available in GUIDE-IT. A fixed effect meta-analysis combined results of both the registry and GUIDE-IT for race. ResultsThe registry had 1010 total HFrEF patients (Black = 509 and White = 501) with 852 having ancestry quantification (>80% Yoruba African Ancestry = 381 and <5% Yoruba African Ancestry = 471). GUIDE-IT had 810 HFrEF patients (Black = 322 and White = 488). There was no significant difference in the association of RAAS inhibitor exposure with heart failure hospitalization by race (meta-analysis p-value for race*RAAS inhibitor exposure interaction = 0.49; Black patients HR [95% CI] for RAAS inhibitor exposure = 0.89 [0.64-1.23)] P = 0.47; White patients = 1.20 (0.83-1.75) P = 0.34). Results were similar when analyzed by ancestry (p-value for ancestry*RAAS inhibitor exposure interaction = 0.57; >80% Yoruba African Ancestry = 0.93 [0.51-1.69] P = 0.80; <5% Yoruba African Ancestry = 1.29 [0.57-2.92] P = 0.54). ConclusionsIn contrast to a previous meta-analysis, this more contemporary analysis of 2 HFrEF patient datasets demonstrates the absence of a racial disparity in RAAS inhibitor associated reductions in heart failure hospitalizations. The difference in this racial disparity over time may be due to improvements in background heart failure therapies, racial differences in healthcare usage, and the use of more advanced statistical approaches.