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

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

Relationship Between Renin, Aldosterone, Aldosterone-to-Renin Ratio and Arterial Stiffness and Left Ventricular Mass Index in Young Adults.

BACKGROUND: Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease. METHODS: The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure. RESULTS: This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P<0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P<0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P<0.001) and 27 (21.0 versus 15.6; P<0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (ß=0.009 [95% CI, 0.001-0.017]; P=0.027) and between aldosterone-to-renin ratio and LVMI in females (ß=0.098 [95% CI, 0.001-0.196]; P=0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age. CONCLUSIONS: Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

Pyridoxal-5'-phosphate: A cost-effective treatment candidate for hypertensive patients?

OBJECTIVES: Because angiotensin (Ang) II is an essential vasoconstrictive peptide, we analyzed the impact of its post-translational modification to pyruvamide-Ang II (Ang P) by pyridoxal-5'-phosphate (PLP) on blood pressure. PLP is a less expensive vitamin B6 derivative and, therefore, could be a cost-effective drug against hypertension. METHODS: Effect of Ang P on calcium ion entry into vascular smooth muscle cells (VSMCs) was analyzed. Binding affinity of Ang P to angiotensin II type 1 receptor (AT1R) was measured. Vasoconstrictive effect of Ang P was investigated using the bioassay of isolated perfused rat kidneys. Spontaneously hypertensive rats (SHR) were administered PLP. Additionally, Wistar Kyoto rats (WKY) received Ang II and PLP. Blood pressure was measured time-dependently. RESULTS: Ang II, incubated with PLP, was post-translationally modified to Ang P. Calcium ion entry in VSMCs was significantly lower with Ang P compared to Ang II. Binding affinity of Ang P to AT1R was lower compared to Ang II. Perfusion pressure of isolated perfused rat kidneys increased less by Ang P than by Ang II. Blood pressure of SHR treated with PLP decreased significantly. Blood pressure of WKY rats treated with Ang II was increased to hypertensive values, whereas blood pressure of WKY rats cotreated with Ang II and PLP was not. CONCLUSION: PLP induces a post-translational modification of Ang II decreasing blood pressure in rats. Assuming that increased PLP intake in the form of vitamin B6 might reduce blood pressure in hypertensive patients, PLP might be a cost-effective drug against hypertension.

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

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

Executive summary of the Spanish consensus for the diagnosis, management, and follow-up of primary hyperaldosteronism.

Primary hyperaldosteronism (PH) is the most common cause of secondary hypertension (HTN) and is associated with a higher cardiometabolic risk than essential HTN. Nevertheless, PH remains clearly underdiagnosed. An early diagnosis and adequate treatment of this disease are essential to reduce the cardiometabolic morbimortality associated with aldosterone excess. PH follow-up is equally essential; however, there is little consensus on how it should be performed, being a topic rarely mentioned by the different clinical practice guidelines. The aim of this executive summary is to summarize the recommendations made in the Spanish consensus of PH for the diagnosis, management, and follow-up of these patients. The Spanish consensus was reached from a multidisciplinary perspective through a nominal group consensus approach by experts from the Spanish Society of Endocrinology and Nutrition (SEEN), the Spanish Society of Cardiology (SEC), the Spanish Society of Nephrology (SEN), the Spanish Society of Internal Medicine (SEMI), the Spanish Society of Radiology (SERAM), the Spanish Society of Vascular and Interventional Radiology (SERVEI), the Spanish Society of Laboratory Medicine (SEQC(ML)), the Spanish Society of Anatomic-Pathology (EAP), and the Spanish Association of Surgeons (AEC).

A Case of Hyponatremic Hypertensive Syndrome With Neurologic Sequelae Secondary to Unilateral Renal Artery Stenosis.

In cases of unilateral renal artery stenosis, acute exacerbations may present as hyponatremic hypertensive syndrome (HHS), a rare and highly morbid complication. Its insidious onset, low incidence, and often counter-intuitive laboratory profile can delay diagnosis and worsen outcomes. Furthermore, complications including end-organ ischemia, polyelectrolyte derangement, and hypertensive crises can occur. Herein, we present a 62-year-old man with known right renal artery stenosis who presented with HHS in hypertensive emergency with encephalopathy. Consideration of the underlying pathomechanism and careful fluid and electrolyte repletion can minimize complications and improve clinical outcomes in this highly morbid and precarious clinical syndrome.

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.

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

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

NTpro-BNP levels in patients with primary hyperaldosteronism and autonomous cortisol co-secretion.

CONTEXT: Patients with primary aldosteronism (PA) have higher cardiac comorbidities including more pronounced left ventricular hypertrophy than patients with essential hypertension. OBJECTIVE: Autonomous cortisol co-secretion (ACS) is a common subtype in PA associated with a worse metabolic profile. HYPOTHESIS: ACS may affect myocardial parameters and result in a worse cardiac outcome compared to patients with PA and without ACS. METHODS: 367 patients with PA undergoing 1mg dexamethasone suppression test (DST) and echocardiography at baseline from two centers of the German Conn´s Registry were included. Follow-up for up to 3.8yrs was available in 192 patients. RESULTS: Patients with PA and ACS had higher NTpro-BNP levels at baseline compared to patients with PA without ACS (114vs75.6pg/ml,p=0.02), but showed no difference in echocardiography values. NTpro-BNP levels showed a significant positive correlation (r=0.141,p=0.011) with cortisol levels after DST at baseline. In response to therapy of PA, NTpro-BNP levels decreased, but remained significantly higher in patients with ACS compared to patients without ACS. At follow-up, left ventricle end diastolic dimension (LVEDD) decreased significantly only in patients without ACS. Left atrial diameter (LAD) decreased significantly in patients without ACS and in female patients with ACS but not in male patients. Left ventricular mass index (LVMI) significantly improved in female patients without ACS but remained unchanged in female patients with ACS as well as in male patients at follow-up. CONCLUSION: In patients with PA, concomitant ACS is associated with a worse cardiac profile and only partial recovery even years after initiation of targeted PA therapy.

Patiromer for Heart Failure Medication Optimization in Patients With Current or Past Hyperkalemia: DIAMOND Subanalysis.

BACKGROUND: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders. OBJECTIVES: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia. METHODS: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK+] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo. RESULTS: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK+ levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: -0.12 (95% CI: -0.17 to -0.07) and -0.08 (95% CI: -0.12 to -0.05), respectively; Pinteraction = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; Pinteraction = 0.031). Adverse events were similar between subgroups. CONCLUSIONS: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK+ control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066).

Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits.

Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT1 receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.

Successful treatment of severe renal failure caused by malignant hypertension using a combination of renin-angiotensin-aldosterone system inhibitors: a case report.

Marked activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in malignant hypertension (MHT) by worsening hypertension and renal function. The rates of readmission for severe hypertension and cardiovascular disease in such emergencies are high, suggesting that suppression of the RAAS may be inadequate during the acute phase in some cases. This report presents a case of MHT complicated with renal insufficiency (creatinine 3.93 mg/dL) and massive proteinuria, in which antihypertensive therapy, including an angiotensin receptor blocker, aliskiren, and spironolactone, normalized blood pressure (BP) and preserved renal function. Plasma renin activity was extremely high (131.9 ng/mL/h) on admission but normalized within almost 2 weeks. Although aliskiren and spironolactone were discontinued before discharge, BP was well controlled and renal function was further improved (creatinine 1.14 mg/dL) at follow-up 24 months later. This case of renal failure induced by MHT was successfully treated with a combination of RAAS inhibitors during the acute phase. The controlled BP and improved renal function in this patient suggest that adequate suppression of the RAAS cascade during the acute phase is potentially effective in terms of breaking the vicious cycle of MHT with hyperreninemia.

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

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

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

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

Molecular Imaging of Renin Activity using Fluorogenic Nanoprobes for Precision Antihypertensive Therapy.

Life-threatening hypertension remains inadequately controlled in clinics due to its heterogenous renin levels. Rapid stratification of hypertension through renin analysis is crucial for effective personalized treatment, yet an ultrasensitive detection approach is currently lacking. Here, we report activatable renin nanoprobes (ARNs) for non-invasive and ultrasensitive profiling of renin activity and guiding antihypertensive treatment decision through near-infrared fluorescence (NIRF) in vivo imaging and in vitro urinalysis. ARNs are intrinsically non-fluorescent due to NIRF reporter connected to a gold nanocluster through a renin-responsive peptide. In hyperreninemia mouse models, ARNs specifically react with renin to liberate the renal clearable NIRF reporter for accurate renin detection that outperforms the gold standard radioimmunoassay. Such specific and sensitive detection also enables imaging-based high-throughput screening of antihypertensive drugs. In hypertensive rat models, ARNs enable ultrasensitive detection of both plasma and urinary renin, facilitating renin-guided precision treatment and significantly improving hypertension control rate (90% versus 58%). Our nanoprobe platform holds great potential for assisting clinicians in rapidly and accurately classifying hypertensive patients and improving outcomes through tailored treatment selection.

The Relationship among SARS-CoV-2, Vaccine Spike Protein, Renin- Angiotensin System, and Epilepsy.

Several comorbidities and illnesses have emerged after the COVID-19 pandemic and the introduction of vaccination based on a slightly modified SARS-CoV-2 spike protein. One of these diseases is epilepsy, where the dysfunctional RAS plays a crucial role in the propagation of the disorder. SARS-CoV-2 infects host cells by utilizing the angiotensin-converting enzyme Type 2 (ACE2) receptor, which allows the virus to infect various cell types, including those in the lungs, nasopharynx, kidneys, lymph nodes, small intestine, stomach, spleen, and brain, leading to widespread organ damage. Once SARS-CoV-2 binds to the ACE2 receptor, it can lead to the overactivation of the ACE/Ang II/AT1R axis. Consequently, higher levels of Ang II activate several deleterious pathways that promote inflammation, contributing to inflammatory responses in the body and exacerbating conditions such as seizures. Additionally, the excitatory effect of AT1R by Ang II excess due to ACE2 inhibition by SARS-CoV-2 or by the vaccine Spike protein may play a further role in the mechanism contributing to epilepsy.

The Relationship between Using Renin-Angiotensin System Inhibitors with Mortality of Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AFib) is a highly prevalent cardiac arrhythmia associated with increased mortality in affected persons. Renin-angiotensin system inhibitors (RASIs) have been suggested as potential therapeutic agents for cardiovascular and renal diseases. OBJECTIVES: However, the relationship between RASIs and mortality in AFib patients remains uncertain. Therefore, the present study was designed and implemented for this purpose. METHODS: We searched PubMed/MEDLINE, Embase, Web of Science (WOS), Cochrane Library, and Scopus databases for studies published until 12 February 2024 with relevant keywords. We included studies that reported mortality outcomes in AFib patients treated with RASIs and non-users. The data extraction and quality assessment processes were conducted, and subgroup analyses and sensitivity analyses were done. The data were analyzed by Stata 15 using statistical tests, such as Chi-square and I2 tests. RESULTS: A total of 15 studies (2007-2024; n=2,178,565 patients) examined the association between RASI drugs and mortality of patients with AFib. The results indicated that compared to the control group, the odds of AFib mortality in the group receiving RASIs were equal to 0.81(95% CI: 0.71-0.92; P-value ≤0.001). The study results did not indicate publication bias (Pvalue= 0.733). During the meta-regression analysis, none of the study variables demonstrated a significant relationship with the observed heterogeneity (P-value > 0.20). Cumulative OR results showed that from 2022 onwards, there was enough evidence to confirm the relationship using RASIs with mortality of patients with AFib. CONCLUSION: Therefore, this meta-analysis suggests that the use of RASI drugs is associated with reduced AFib mortality. However, the authors emphasize the need for further high-quality studies and large-scale randomized clinical trials to validate these findings.

Walnut peptide relieves hypertension and associated kidney and heart injury by regulating the renin-angiotensin-aldosterone system and intestinal microbiota.

BACKGROUND: Hypertension is a chronic disease with high morbidity and mortality. Previously, we screened a walnut meal peptide FDWLR (PEP) with significant angiotensin-converting enzyme inhibitory activity. The present study further investigated the anti-hypertensive effects of PEP in vivo using spontaneously hypertensive rats. RESULTS: The results indicated that PEP reduced blood pressure and the indices in the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme (ACE) (decreased by 15.36%), angiotensin II (Ang II) (decreased by 31.56%), angiotensinogen (AGT) (decreased by 58.84%) and aldosterone (ALD) (decreased by 18.27%), whereas NO levels increased by 54.96%. The pathological analysis showed that PEP relieved cardiac and renal damage. PEP also alleviated oxidative stress, inflammation and fibrosis in the heart and kidney. Mechanistically, PEP mitigated cardiac and renal damage by simultaneously regulating ACE-Ang II-AT1R and the ACE2-Ang (1-7)-MAS axis. Additionally, PEP increased the levels of short chain fatty acids by 224.16% and improved gut microbiota by increasing the abundance of Prevotella, Phascolarctobacterium, Clostridium_sensu_stricto and Bifidobacterium, at the same time as decreasing Bacteroides and Alistipes abundances. CONCLUSION: This study indicated that PEP prevented hypertension and associated heart and kidney damage by modulating the RAAS system and gut microbiota, which is valuable in guiding future development and optimal utilization of walnut meal. © 2024 Society of Chemical Industry.

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

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