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AbstractObjectveMaterials and MethodsResultsConclusionThe purpose of the research was to investigate the effects of aerobic training on renal function, oxidative stress, intrarenal renin–angiotensin system, and mortality of hypertensive and diabetic (SHR-STZ) rats.Blood pressure, creatinine, urea levels, urinary glucose, urine volume, and protein excretion were reduced in trained SHR-STZ rats.Aerobic training not only attenuated oxidative stress but also elevated the activity of antioxidant enzymes in the kid′ney of SHR-STZ rats. Training increased intrarenal levels of angiotensin-converting enzymes (ACE and ACE2) as well as the neprilysin (NEP) activity, along with decreased intrarenal angiotensin II (Ang II) levels. Aerobic training significantly improved the survival of STZ-SHR rats.The protective role of aerobic training was associated with improvements in the renal antioxidative capacity, reduced urinary protein excretion along with reduced intrarenal Ang II and increased NEP activity. These findings might reflect a better survival under the combined pathological conditions, hypertension, and diabetes. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) is an immunosuppressive drug, used in organ transplantations. Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in CsA-toxicity. Glycine (Gly) has antioxidant and anti-inflammatory effects. In this study, Gly was investigated for its protective role against CsA-induced toxicity. CsA (20 mg/kg/day; subcutaneously) was administered to rats along with Gly injection (250 or 1000 mg/kg; intraperitoneally) for 21 days. Renal function markers [serum urea and creatinine and urinary protein and kidney injury molecule levels and creatinine clearance values] together with histopathological examinations were performed. Oxidative stress (reactive oxygen species, thiobarbutiric acid reactive substances, advanced oxidation products of protein, glutathione, ferric reducing anti-oxidant power and 4-hydroxynonenal levels), and inflammation (myeloperoxidase activity) were determined in kidney tissue. The RAS system [angiotensin II (Ang II) levels, and mRNA expressions of angiotensin converting enzyme (ACE), angiotensin II type-I receptor (AT1R)] and NADPH-oxidase 4 (NOX4) were measured in kidney and aorta. CsA caused significant disturbances in renal function markers, increases in oxidative stress and inflammation parameters and renal damage. Serum angiotensin II levels and mRNA expressions of ACE, AT1R and NOX4 elevated in the aorta and kidney of CsA-rats. Gly, especially its high-dose, alleviated renal function markers, oxidative stress, inflammation and renal damage in CsA-rats. Moreover, serum Ang II levels and mRNA expressions of ACE, AT1R and NOX4 decreased significantly in aorta and kidney in CsA-rats due to Gly treatment. Our results indicate that Gly may be useful for the prevention of CsA-induced renal and vascular toxicity. [ABSTRACT FROM AUTHOR]

IgA nephropathy is one of the most common forms of glomerular disease. Patients with persistent proteinuria are at increased risk of progression to kidney failure. There is a significant need for safe and effective therapies to lower proteinuria in these patients. Sparsentan is a non-immunosuppressive agent that acts as a dual angiotensin and endothelin receptor antagonist. It lowers proteinuria in experimental models of glomerular disease and in affected patients. This review covers the immunological and non-immunological actions of sparsentan in glomerular disease. It reviews the clinical trials that evaluated the impact of the drug in pediatric and adult patients with IgA nephropathy. It places the use of sparsentan in an overall treatment paradigm for the full spectrum of patients with IgA nephropathy including nonspecific renoprotective agents such as inhibitors of the renin-angiotensin-aldosterone axis and SGLT2 transporter and immunosuppressive drugs. The review represents a search of the current literature about the effect of the drug on normal physiology and the pathogenesis of IgA nephropathy. The safety, tolerability, and therapeutic efficacy of sparsentan have been demonstrated in long-term studies of patients with primary glomerular diseases extending over 5 years. The evidence in support of a beneficial treatment effect of sparsentan is stronger in IgAN than in FSGS. It is anticipated that sparsentan will supplant the use of ACEI or ARB as the first-line therapy to reduce proteinuria prior to the implementation of immunosuppressive agents in patients with IgA nephropathy. It may be combined with other renoprotective drugs like SGLT2 inhibitors. Practice guidelines are needed to promote safe and effective use of this new drug by nephrologists caring for patients with IgAN in all clinical settings. [ABSTRACT FROM AUTHOR]

Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD). JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs. When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb. The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD. [ABSTRACT FROM AUTHOR]

Di-(2-ethylhexyl) phthalate (DEHP) is used in food packaging and medical products, resulting in unintentional human ingestion. Concurrently, a high fat (HF)-oriented diet is very popular for many people worldwide. Here we investigated the regulatory role of renin-angiotensin system in kidney dysfunction. The HF diet-fed rats were fed a HF diet plus different doses of 10, 100 and 300 mg/kg bw DEHP for 35 days by gavage. Serum lipid contents and protein activities of renin-angiotensin system (RAS) components were measured using biochemical methods and ELISA; key metabolic genes and proteins of the kidney were determined by RT-PCR and western blotting techniques. Kidney morphology was examined through hematoxylin-eosin (HE) staining. Kidney weight to body weight ratio and mRNA expression of kidney damage markers were significantly increased following DEHP plus HF administration, which corresponded histologically with glomerular basement membrane thickening and glomerular swelling. Furthermore, DEHP treatment plus a HF diet induced dyslipidemia, accompanied by increased levels of renin-angiotensin system components, such as ACE protein, MAS-1 protein, serum renin and aldosterone. In addition, mRNA expression levels of pro-inflammatory cytokines were significantly upregulated in the kidneys. Pearson correlation analysis revealed that higher kidney ACE expression and ACE/ACE-2 ratio were positively associated with TG, TC and LDL-C levels. These data suggest that combined exposure to DEHP exposure plus a HF diet feeding may induce renal damage through overactivation of RAS. [ABSTRACT FROM AUTHOR]

This article explores the collaborative management of volume status, hypertension, and immunosuppression in kidney transplant patients to improve their outcomes. It discusses the risks associated with accepting marginal kidneys and the increasing rates of delayed or slow graft function. The article emphasizes the importance of multidisciplinary approaches to prevent complications such as hypertension, volume overload, and graft failure. It also discusses various methods for assessing volume status, including diagnostic techniques and ultrasonography. The article proposes a stepwise approach for managing volume status, hypertension, and immunosuppressive medications in the peri-transplant period. It also addresses the management of post-transplant patients with delayed or slow graft function, suggesting the potential benefits of once or twice weekly dialysis. The article highlights the importance of communication between community nephrologists and the transplant team and recommends the use of immediate-release calcineurin inhibitors over extended-release formulations. It acknowledges regional variations in dialysis laws and emphasizes the need for frequent clinical assessments for patients with delayed or slow graft function. Overall, the article provides a comprehensive management scheme for pre- and post-transplantation care and emphasizes the importance of personalized and collaborative approaches to optimize patient outcomes. [Extracted from the article]

The exponential increase in the prevalence of prediabetes has become a global concern due to the comorbidities and mortality rates that are positively associated with it. The incidence of prediabetes is directly proportional to the prevalence of comorbidities with risk factors such as insulin resistance, adiposity, lipotoxicity, obesity and the alteration of the renin-angiotensin-aldosterone system. Hence, the current study systematically reviewed and performed a meta-analysis of these risk factors, their clinical indicators and the RAAS components. This systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-2020) standards. This was accomplished by searching clinical MeSH categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers examined all the findings and selected the studies that satisfied the inclusion criteria. The Downs and Black Checklist was used to assess for bias, followed by a Review Manager v5. A Forrest plot was used for the meta-analysis and sensitivity analysis. The protocol for this review was registered with PROSPERO CRD42022320252. The clinical studies (n = 2) comprised 1065 patients with prediabetes and 1103 normal controls. The RAAS measurements were completed in the adipose tissue. The RAAS components, renin and aldosterone were higher in the prediabetic (PD) compared to the control [mean difference (MD) = 0.16, 95% CI 0.16 (−0.13, 0.45), p = 0.25]. Furthermore, the PD group demonstrated higher triglycerides mean difference [MD = 7.84, 95% CI 7.84 (−9.84, 25.51), p = 0.38] and increased BMI [MD = 0.13, 95% CI 0.13 (−0.74, 0.99), p = 0.77] compared to the control. The overall quality of the studies was fair with a median score and range of 17 (16–18). The current study highlights the relationship between increased BMI, RAAS and insulin resistance which is a predictor of prediabetes. The renin is slightly higher in the prediabetes group without any statistical significance, aldosterone is rather negatively associated with prediabetes which may be attributed to the use of anti-hypertensive treatment. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) operates within adipose tissue. Obesity-related changes can affect adipose RAS, predisposing to hypertension, type 2 diabetes, and possibly severe COVID-19. We evaluated the in vitro research on human adipose RAS and identified gaps in the literature. Medline (Ovid), Embase (Ovid), Web of Science, Scopus, and 1findr were searched to identify relevant studies. Fifty primary studies met our inclusion criteria for analysis. Expression of RAS components (n = 14), role in differentiation (n = 14), association with inflammation (n = 15) or blood pressure (n = 7) were investigated. We found (1) obesity-related changes in RAS were frequently studied (30%); (2) an upswing of articles investigating adipose ACE-2 expression since the COVID-19 pandemic; (3) a paucity of papers on AT2R and Ang (1–7)/MasR which counterbalance Ang II/ART1; (4) weight loss lowered adipose ACE-2 mRNA expression; and (5) angiotensin receptor blockers (ARBs) reduced deleterious effects of angiotensin II. Overall, these studies link Ang II/ATR1 signalling to impaired adipogenesis and a pro-inflammatory dysfunctional adipose tissue, with ATR1 blockade limiting these responses. ACE-2 may mitigate Ang II effects by converting it to Ang(1–7) which binds MasR. More work is needed to understand adipose RAS in various pathologic states such as obesity and COVID-19 infection.T. [ABSTRACT FROM AUTHOR]

Background: Hypertensive intracerebral hemorrhage (HICH) is a life-threatening disease and lacks effective treatments. Previous studies have confirmed that metabolic profiles altered after ischemic stroke, but how brain metabolism changes after HICH was unclear. This study aimed to explore the metabolic profiles after HICH and the therapeutic effects of soyasaponin I on HICH. Methods: HICH model was established first. Hematoxylin and eosin staining was used to estimate the pathological changes after HICH. Western blot and Evans blue extravasation assay were applied to determine the integrity of the blood-brain barrier (BBB). Enzyme-linked immunosorbent assay was used to detect the activation of the renin-angiotensin-aldosterone system (RAAS). Next, liquid chromatography-mass spectrometry-untargeted metabolomics was utilized to analyze the metabolic profiles of brain tissues after HICH. Finally, soyasaponin I was administered to HICH rats, and the severity of HICH and activation of the RAAS were further assessed. Results: We successfully constructed HICH model. HICH significantly impaired BBB integrity and activated RAAS. HICH increased PE(14:0/24:1(15Z)), arachidonoyl serinol, PS(18:0/22:6(4Z, 7Z, 10Z, 13Z, 16Z, and 19Z)), PS(20:1(11Z)/20:5(5Z, 8Z, 11Z, 14Z, and 17Z)), glucose 1-phosphate, etc., in the brain, whereas decreased creatine, tripamide, D-N-(carboxyacetyl)alanine, N-acetylaspartate, N-acetylaspartylglutamic acid, and so on in the hemorrhagic hemisphere. Cerebral soyasaponin I was found to be downregulated after HICH and supplementation of soyasaponin I inactivated the RAAS and alleviated HICH. Conclusion: The metabolic profiles of the brains changed after HICH. Soyasaponin I alleviated HICH via inhibiting the RAAS and may serve as an effective drug for the treatment of HICH in the future. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of hypertension. However, the underlying mechanisms for lowering blood pressure (BP) by suppressing ER stress remain unclear. Here, we hypothesized that inhibition of ER stress could restore the balance between RAS components and lower BP in spontaneously hypertensive rats (SHRs). Methods: Wistar-Kyoto (WKY) rats and SHRs received vehicle or 4-PBA, an ER stress inhibitor, in the drinking water for 4 weeks. BP was measured by tail-cuff plethysmography, and the expression of RAS components was examined by Western blot. Results: Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure and increased renal ER stress and oxidative stress, accompanied by impaired diuresis and natriuresis. Moreover, SHRs had higher ACE and AT1R and lower AT2R, ACE2, and MasR expressions in the kidney. Interestingly, 4-PBA treatment improved impaired diuresis and natriuresis and lowered blood pressure in SHRs, accompanied by reducing ACE and AT1R protein expression and increasing AT2R, ACE2, and MasR expression in the kidneys of SHRs. In addition, these changes were associated with the reduction of ER stress and oxidative stress. Conclusions: These results suggest that the imbalance of renal RAS components was associated with increased ER stress in SHRs. Inhibition of ER stress with 4-PBA reversed the imbalance of renal RAS components and restored the impaired diuresis and natriuresis, which, at least in part, explains the blood pressure-lowering effects of 4-PBA in hypertension. [ABSTRACT FROM AUTHOR]

The aetiological mechanism of preeclampsia (PE) is unclear exactly, so we attempted to investigate the association between susceptibility to preeclampsia and renin-angiotensin-aldosterone system (RAAS) gene polymorphisms to explore the aetiology in terms of genetics. A systematic search was performed in electronic databases to identify relevant studies. Eventually 73 studies were enrolled, odds ratios were generated by 5 genetic models. In overall analysis, significant associations were detected for AGT M235T, AT1R A1166C and CYP11B2 C344T whereas negative correlation was shown for AGT T174M. As stratified by race and geography, AGT 235T allele and AT1R 1166C allele increased preeclampsia risk and AGT T174M was justified uncorrelated with preeclampsia. Our meta-analysis illustrated that AGT 235T allele and AT1R 1166C allele increased and CYP11B2 344T allele decreased preeclampsia risk while AGT T174M polymorphism did not change preeclampsia risk. Hence, pregnant women carrying high-risk genotypes need strengthened management to prevent and early identification of preeclampsia. [ABSTRACT FROM AUTHOR]

To evaluate the clinical utility of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in foetuses with oligohydramnios. In this retrospective study, 126 fetuses with oligohydramnios at our centre from 2018 to 2021 were reviewed. The results of CMA and WES were analysed. One hundred and twenty-four cases underwent CMA and 32 cases underwent WES. The detection rate of pathogenic/likely pathogenic (P/LP) copy number variant (CNV) by CMA was 1.6% (2/124). WES revealed P/LP variants in 21.8% (7/32) of the foetuses. Six (85.7%, 6/7) foetuses showed an autosomal recessive inheritance pattern. Three (42.9%, 3/7) variants were involved in the renin–angiotensin–aldosterone system (RAAS), which are the known genetic causes of autosomal recessive renal tubular dysgenesis (ARRTD). CMA has low diagnostic utility for oligohydramnios, while WES offers obvious advantages in improving the detection rate. WES should be recommended for fetuses with oligohydramnios. CMA has low diagnostic utility for oligohydramnios. WES offers obvious advantages for improving the detection over CMA, which improves pregnancy management, prenatal counselling and recurrence risk assessment for future pregnancies. [ABSTRACT FROM AUTHOR]

Hyponatraemia and Vitamin D deficiency are common conditions in older adults. Both conditions cause bone fragility and gait abnormalities, which are risk factors for falls and poor health outcomes in older adults. Vitamin D deficiency is a risk factor for osteoporosis and increases the risk for fragility fractures. Hyponatraemia, the commonest electrolyte abnormality, causes bone resorption and contributes to falls by impairing cognition and by causing gait abnormalities. Sodium homeostasis is complex and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), a diagnosis of exclusion, is one of the most common causes of hyponatraemia. Instability is a feared geriatric syndrome, as falls can have devastating consequences for the older adult, leading to significant morbidity and mortality. Previous studies have shown that patients with hyponatraemia had a higher rate of vitamin D deficiency and, conversely, those with vitamin D deficiency had a higher rate of hyponatraemia. The exact pathophysiological mechanism behind this correlation is unclear but may involve bone derived hormone fibroblast growth factor 23 and the renin–angiotensin–aldosterone system. A case of an 83-year-old Asian female, who presented with an osteoporotic intertrochanteric femoral fracture following a fall, is presented. She was found to have chronic hyponatraemia and was subsequently diagnosed with SIADH due to vitamin D deficiency. [ABSTRACT FROM AUTHOR]

Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA (small interfering ribonucleic acid) therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, and durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach. This article describes the molecular basis for durability over months and the 24-h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a siRNA targeting hepatic angiotensinogen, which reduces blood pressure (BP) by up to 20 mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran. Further studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime BP due to 24-h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) cannot be considered an isolated disease. Patients with AF should be managed using a comprehensive approach that is not limited to stroke prevention. In this manuscript, the potential role of AF as a vascular disease that is managed as part of a holistic approach was reviewed. The residual risk of stroke in patients with AF reaches 1–2% annually, despite appropriate anticoagulation therapy. Additionally, patients with AF may develop cognitive impairment through stroke-independent pathways. Furthermore, patients with AF may have a higher risk of developing atherosclerotic vascular disease in various vascular beds and chronic kidney disease; conversely, patients with atherosclerotic disease may have an increased risk of developing AF. AF should be considered a truly systemic vascular disease, since it brings together several hemodynamic and systemic changes, including inflammation, oxidative stress, activation of the renin-angiotensin-aldosterone and sympathetic systems, as well as a prothrombotic state and endothelial dysfunction. In this regard, patients with AF should be treated based on a holistic approach that is not limited to oral anticoagulation but includes complete vascular protection. [ABSTRACT FROM AUTHOR]

Worsening heart failure (HF) is associated with a high risk of death and rehospitalization. Despite that, real world evidence about the impact of worsening HF on clinical practice is scarce. A narrative review about registries addressing recent worsening HF events in Spain, with special emphasis on patients recently hospitalized for HF was performed. Worsening HF can be defined as situations where the patient's HF deteriorates to the extent that it necessitates initiation or intensification of diuretic treatment (mainly intravenous). The events can occur at the outpatient level, generally in the day hospital, in the emergency department or even hospitalization. Early identification of worsening HF events is essential to establish appropriate treatment as soon as possible. In this context, robust clinical benefits have been reported for renin-angiotensin system inhibitors, sacubitril-valsartan, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors, and vericiguat. In Spain, several registries of patients with HF have been developed, some of them including patients recently hospitalized for HF, but not with recent worsening HF events. Therefore, registries addressing recent worsening events would be desirable. Using a practical approach, this review analyzes the importance of worsening HF events, with special emphasis on Spanish data. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association between dose reduction of renin-angiotensin-aldosterone system inhibitors (RAASis) and Acute kidney injury (AKI). AKI, which is commonly observed in hospitalized patients, increases mortality. Although RAASis and coronary artery angiography (CAG) are reported to be risk factors for AKI, whether dose reduction of RAASis can prevent AKI after CAG remains unknown. In this retrospective propensity score (PS)-matched cohort from the RWD database, which includes 20 million patients from 190 hospitals in Japan, we examined the impact of dose reduction of RAASis on the development of AKI after CAG. The subjects were patients with an estimated glomerular filtration rate (eGFR) of 15–60 mL/min/1.73 m2, and the exposure of interest was the presence of a dose reduction in RAASis within 3 days before CAG was performed. Propensity score matching was performed with 19 baseline characteristics using a logistic regression model. We identified 3329 patients who were prescribed RAASis at least one month before admission and underwent CAG. Six hundred seventy-four patients had a dose reduction 3 days prior to undergoing CAG, and 2655 patients did not. AKI was observed in 34 (5.0%) patients in the reduction group and 137 (5.2%) patients in the control group. There was no significant difference in the primary outcome between the two groups in the PS-matched cohort (OR: 1.08, 95% CI: 0.70–1.66). A reduction in the dose of RAASis did not prevent the development of AKI among patients undergoing CAG. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) are at high risk of CKD progression and cardiovascular events. Despite treatment with renin-angiotensin system inhibitors and SGLT-2 inhibitors, the residual risk is substantial. There is preclinical and clinical evidence supporting a key role of mineralocorticoid receptor in cardiorenal injury in T2DM. Finerenone is a selective and nonsteroidal mineralocorticoid receptor antagonist that reduces -on preclinical studies- heart and kidney inflammation and fibrosis. Clinical trials have demonstrated that among patients with T2DM and CKD, finerenone reduces CKD progression and the risk of cardiovascular events. The incidence of adverse events is similar than for placebo. Permanent discontinuation of study drug due to hyperkalemia was low (1.7% of finerenone and 0.6% of placebo participants) as was the risk of hyperkalemia-related severe-adverse events (1.1%). We provide an overview of risk factors for hyperkalemia and management of serum potassium in people with CKD and T2DM on finerenone. As finerenone increases potassium levels in a predictable way, patients at risk of hyperkalemia can be identified early in clinical practice and monitored for an easy management. This will allow people with T2DM and CKD to safely benefit from improved cardiorenal outcomes. [ABSTRACT FROM AUTHOR]

The pathophysiology of heart failure with reduced ejection fraction (HFrEF) is a complex process in which a number of neurohormonal systems are involved. Targeting only some of these systems, but not all, translates into a partial benefit of HF treatment. The nitric oxide-soluble guanylate cyclase (sGC)-cGMP pathway is impaired in HF, leading to cardiac, vascular and renal disturbances. Vericiguat is a once-daily oral stimulator of sGC that restores this system. No other disease-modifying HF drugs act on this system. Despite guidelines recommendations, a substantial proportion of patients are not taking all recommended drugs or when taking them, they do so at low doses, limiting their potential benefits. In this context, treatment should be optimized considering different parameters, such as blood pressure, heart rate, renal function, or potassium, as they may interfere with their implementation at the recommended doses. The VICTORIA trial showed that adding vericiguat to standard therapy in patients with HFrEF significantly reduced the risk of cardiovascular death or HF hospitalization by 10% (NNT 24). Furthermore, vericiguat does not interfere with heart rate, renal function or potassium, making it particularly useful for improving the prognosis of patients with HFrEF in specific settings and clinical profiles. [ABSTRACT FROM AUTHOR]

To study associations between the first-trimester maternal determinants of renin-angiotensin-aldosterone system (RAAS) activation and telomere length (TL) in pregnancies conceived natural and after IVF/ICSI. In 145 pregnancies of the Rotterdam Periconception cohort renin, prorenin and aldosterone concentrations were measured in maternal blood at 9 weeks gestational age (GA). TL was measured by qPCR at 20 weeks GA. A significantly negative correlation was found between renin and TL, which was attenuated for prorenin but not observed for aldosterone. Maternal TL was significantly shorter in pregnancies conceived after in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) compared to natural pregnancies. The negative association between first-trimester maternal renin and maternal TL, and the shorter maternal TL in women after IVF/ICSI treatment compared to natural pregnancies, substantiates the role of excessive RAAS activation. [ABSTRACT FROM AUTHOR]

Purpose: As of November 28, 2020, COVID-19 has been reported in 220 countries with 61,036,793 confirmed cases and 1,433,316 confirmed deaths; countries became vigilant around the world. In addition to SARS-CoV-2 causing pneumonia, many studies have reported ischemic stroke in patients with COVID-19. This article describes the effects and possible underlying mechanisms of SARS-CoV-2 on ischemic stroke. Materials and methods: A literature search was performed using PubMed, Web of Science, and other COVID-dedicated databases and the combination of the keywords 'SARS-CoV-2', 'COVID-19' and 'ischemic stroke' up to November 28, 2020. Results: SARS-CoV-2 invades the host through angiotensin converting enzyme 2 (ACE2). ACE2 is expressed not only in the lungs, but also in the brain and vascular endothelial cells. SARS-CoV-2 infection might cause direct vascular disease or enhance the immunogenic thrombosis environment through several mechanisms. SARS-CoV-2 infection can modulate the host immune response and can cause inflammation, coagulation disorders, renin angiotensin system disorders, hypoxia, and stress disorders, which may lead to the occurrence of ischemic stroke. Conclusions: Some patients with COVID-19 can develop ischemic stroke. Ischemic stroke has a high risk of causing disability and is associated with a high mortality rate. It is hoped that when medical staff treat patients with COVID-19, they would pay attention to the occurrence of ischemic stroke to improve the prognosis of patients with COVID-19. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) is an infectious disease caused by a new virus that causes respiratory illness. Older adults and individuals who have pre-existing chronic medical conditions are at higher risk for more serious complications from COVID-19. Hypovitaminosis D is attributed to the increased risk of lung injury and acute respiratory distress syndrome (ARDS) as well as diabetes, cardiovascular events and associated comorbidities, which are the main causes of severe clinical complications in COVID-19 patients. Considering the defensive role of vitamin D, mediated through modulation of the innate and adaptive immune system as well as inhibition of the Renin Angiotensin System (RAS), vitamin D supplementation might boost the immune system of COVID-19 patients and reduce severity of the disease in vitamin D deficient individuals. [ABSTRACT FROM AUTHOR]

While coronavirus disease 2019 (COVID-19) begins as a respiratory infection, it progresses as a systemic disease involving multiorgan microthromboses that underly the pathology. SARS-CoV-2 enters host cells via attachment to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is widely expressed in a multitude of tissues, including the lung (alveolar cells), heart, intestine, kidney, testis, gallbladder, vasculature (endothelial cells), and immune cells. Interference in ACE2 signaling could drive the aforementioned systemic pathologies, such as endothelial dysfunction, microthromboses, and systemic inflammation, that are typically seen in patients with severe COVID-19. ACE2 is a component of the renin–angiotensin system (RAS) and is intimately associated with the plasma kallikrein-kinin system (KKS). As many papers are published on the role of ACE and ACE2 in COVID-19, we will review the role of bradykinin, and more broadly the KSS, in SARS-CoV-2-induced vascular dysfunction. Furthermore, we will discuss the possible therapeutic interventions that are approved and in development for the following targets: coagulation factor XII (FXII), tissue kallikrein (KLK1), plasma kallikrein (KLKB1), bradykinin (BK), plasminogen activator inhibitor (PAI-1), bradykinin B1 receptor (BKB1R), bradykinin B2 receptor (BKB2R), ACE, furin, and the NLRP3 inflammasome. Understanding these targets may prove of value in the treatment of COVID-19 as well as in other virus-induced coagulopathies in the future. [ABSTRACT FROM AUTHOR]

While a consistent, gradual decline in the renal glomerular filtration rate (GFR) is a characteristic occurrence over the human life span, the exact pathophysiology behind this event remains unresolved. Evidence to date suggests that the endogenous glucose-insulin system could be involved at some level. Diabetic-induced nephropathy, one of the most prevalent chronic renal diseases, is closely linked to a severe form of insulin resistance (IR). Nevertheless, it is less certain that the ubiquitous milder forms of IR in nondiabetics ascribed customarily to routine, poor choices in diet and exercise management can over time diminish GFR and adversely influence other renal functions to any perceptible extent. Baseline data for cross-sectional analyses were obtained from a cohort of healthy, nondiabetic volunteers (fasting blood glucose [FBG] ≤ 125 mg/dL) involved in prior clinical studies. Slope-based rather than threshold analyses were mainly employed. These measurements were applied for the most part to correlate age, FBG levels used as an estimate of IR activity, and systolic blood pressure (SBP) to a variety of metabolic parameters during aging with a primary focus on GFR. Considering cause and effect, FBG and SBP correlate positively with the diminishing GFR over a major part of the life span. The decline in GFR begins somewhere around the mid-20s and coincides with key temporal increases in FBG and SBP levels. A close time-based setting suggests that IR plays a prominent role in the declining GFR that occurs over the life span. This is perhaps due in part through deleterious effects of rising levels of insulin, glucose, and SBP individually or combined that are also popular proposed causative factors for human aging in general. On the philosophical side, the latter fact suggests that the declining GFR might provide a practical way to estimate the rate of overall human biological aging. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan–Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835–76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078–0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047–0.689; p = 0.012) was further reduced. NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S), an endogenous gaseous signaling transmitter, has gained recognition for its physiological effects. In this review, we aim to summarize and discuss existing studies about the roles of H2S in renal functions and renal disease as well as the underlying mechanisms. H2S is mainly produced by four pathways, and the kidneys are major H2S–producing organs. Previous studies have shown that H2S can impact multiple signaling pathways via sulfhydration. In renal physiology, H2S promotes kidney excretion, regulates renin release and increases ATP production as a sensor for oxygen. H2S is also involved in the development of kidney disease. H2S has been implicated in renal ischemia/reperfusion and cisplatin–and sepsis–induced kidney disease. In chronic kidney diseases, especially diabetic nephropathy, hypertensive nephropathy and obstructive kidney disease, H2S attenuates disease progression by regulating oxidative stress, inflammation and the renin–angiotensin–aldosterone system. Despite accumulating evidence from experimental studies suggesting the potential roles of H2S donors in the treatment of kidney disease, these results need further clinical translation. Therefore, expanding the understanding of H2S can not only promote our further understanding of renal physiology but also lay a foundation for transforming H2S into a target for specific kidney diseases. [ABSTRACT FROM AUTHOR]

Mineral and bone disorder biomarkers 'normal ranges' are controversial. The aim of the study was to evaluate the association between serum calcium (Ca), phosphate (P), intact parathyroid hormone (iPTH), and 25(OH) vitamin D levels and mortality risk, in a chronic kidney disease (CKD) grade (G) 3b-4 cohort. The Uruguayan National Renal Healthcare Program (NRHP-UY) CKD patients' cohort, included between 1 October 2004 and 1 March 2020 and followed-up until 1 March 2021, was analyzed with the Ethics Committee approval. A total of 6473 patients were analyzed: 56% men, median age 73 (65–79) years, 55% on CKD G3b. At the end of the follow-up, 2459 (37.7%) patients had died (6.4/100 patient–year). There were iPTH data on 2013 patients (younger, with lower estimated glomerular filtration rate (eGFR) and lesser comorbidities). By bivariate Cox analysis the lowest death risk was observed with mean Ca between 9.01 and 10.25 mg/dl, P between 2.76 and 4.0 mg/dl, iPTH ≤ 105 pg/ml, and 25(OH) vitamin D >10 ng/ml. The multivariate Cox regression mortality risk adjusted to age, sex, CKD etiology, diabetes, smoking, cardiovascular comorbidity, blood pressure, proteinuria, eGFR, renin-angiotensin system blockers and vitamin D treatments, serum Ca, P, iPTH, and 25(OH) vitamin D (n = 964) showed that a higher mortality risk was associated with p > 4.00 mg/dl (HR 1.668, CI 95%: 1.201–2.317), iPTH >105 pg/ml (HR 1.386, CI 95%: 1.012–1.989), and 25(OH) vitamin D ≤ 10 ng/ml (HR 1.958, CI 95%: 1.238–3.098) and a lower mortality risk with 1,25(OH)2 vitamin D treatment (HR 0.639, CI 95%: 0.451–0.906). These data may contribute to the precise G3b-4 CKD-MBD biomarkers levels definition. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) has been well studied among young people, but few data on clinicopathological characteristics, treatment response and outcomes for elderly IgAN patients are available. A cohort study of elderly IgAN patients was performed. The combined endpoints of renal outcome were a 50% decline in eGFR compared with the time of renal biopsy, end-stage kidney disease and/or death. Risk factors associated with poor renal outcomes were then determined. The benefits of immunosuppressant therapies were also evaluated by Kaplan-Meier survival curve analysis. This study ultimately included 126 elderly patients with IgAN. Comparison between the endpoint and non-endpoint groups indicated that patients with poor outcomes had more severe clinical features, such as worse kidney function, severe hematuria and lower albumin levels. Cox regression analysis indicated that age (HR 1.15, 95% CI 1.02–1.29, p = 0.021), male gender (HR 9.71, 95% CI 1.00–97.56, p = 0.050), and urine red blood cells (HR 1.003, 95% CI 1.000–1.006, p = 0.029) were independent risk factors for poor renal outcome in elderly IgAN patients. To explore possible reasons accounting for the predictive value of age and sex, patients were divided into two groups based on these two variables. Patients in the geriatric group had lower serum albumin, estimated glomerular filtration rate, hemoglobin and aspartate aminotransferase levels than those in the quinquagenarian group. Male patients tended to have higher hemoglobin, higher alanine aminotransferase, and lower triglycerides and cholesterol levels than female patients. To investigate different treatment responses, patients were classified into two groups depending on treatment strategies (renin-angiotensin system inhibitors and immunosuppressive therapy), and the survival analysis indicated no significant difference in kidney outcome between the two groups (p > 0.05). This result still holds after adjusting for age, sex, eGFR, hematuria, and proteinuria. Advanced age, male, and hematuria might be independently associated with poor kidney outcomes in elderly patients with IgAN. Immunosuppressive therapy might confer no overall benefit to older IgAN patients. [ABSTRACT FROM AUTHOR]

The value of anti-phospholipase A2 receptor antibody (anti-PLA2R ab) monitoring at 3 months after diagnosis in membranous nephropathy (MN) remains uncertain. We retrospectively examined the outcome on 1 August 2020 of 59 adult patients (age 54 (44, 68) years, 69% male, SCr 1.0 (0.9, 1.3) mg/dL) diagnosed with MN (kidney biopsy, positive serum anti-PLA2R ab). The outcomes were: kidney survival; partial and/or complete remission. Most of the studied patients (97%) received immunosuppression, cyclophosphamide regimens were the most frequent (87%), followed by cyclosporine (10%). The median time to remission was 12.0 months and the cumulative remission rates were 34% at 6, 54% at 12, and 73% at 24 months. Forty (69%) patients had negative anti-PLA2R ab at 3 months, they had similar age, serum creatinine, albumin, proteinuria, and treatment with the group with positive ab at 3 months. In the Cox proportional hazard model, three months anti-PLA2R ab negativization (HR 0.4 (95%CI 0.1, 0.9)) was an independent predictor for remission, while baseline hypoalbuminemia (HR 3.0 (95%CI 1.5, 5.7)) was associated with absence of remission. Six (10%) patients died, mostly due to cardiovascular disease and infections. A total of five (9%) patients started dialysis. Mean kidney survival time was 50.3 months and there was no survival difference in relation to baseline anti-PLA2R ab titer (p.09) or 3 months negativization (p.8). Three months anti-PLA2R ab negativization seems to be a late predictor of remission, and lower serum albumin at diagnosis is an early marker for remission absence. Abbreviations: anti-P LA2R ab, anti-phospholipase A2 receptor antibody; eGFR, estimated glomerular filtration rate; ESKD, end stage kidney disease; MN, membranous nephropathy; NELL-1, neural epidermal growth factor-like 1 protein; RAAS: renin–angiotensin–aldosterone system; RBC: red blood cells; RRT, renal replacement therapy; T HSD7A, thrombospondin type-1 domain containing 7A [ABSTRACT FROM AUTHOR]

Background. Chronic peritoneal dialysis (PD) patients often develop hypokalemia but less commonly hyperkalemia. Methods. We explored incidence and mechanisms of hyperkalemia in 779 serum samples from 33 patients on PD for 1 − 59 months. Normal serum potassium concentration was defined as 3.5 − 5.1 meq/l. Results. Mean monthly serum potassium concentrations were normal (except for 1 month), but we observed hypokalemia (<3.5 meq/l) in 5% and hyperkalemia (>5.1 meq/l) in 14% of 779 serum samples. Incidence of hyperkalemia did not change over time on PD: Year 1 (15%), Year 2 (11%), Year 3 (19%), Years 4–5 (22%). Hyperkalemia was mostly modest but occasionally extreme [5.2–5.4 meq/l (55%), 5.5–5.7 meq/l (21%), 5.8–6.0 meq/l (10%), >6.0 meq/l (14%)]. Of 31 patients (2 excluded due to brief PD time), 39% displayed hyperkalemia only, 23% displayed hypokalemia only, and the remainder (38%) displayed both or neither. Comparing hypokalemia-only with hyperkalemia-only patients, we found no difference in potassium chloride therapy, medications interrupting the renin-angiotensin system, small-molecule transport status, and renal urea clearance. We compared biochemical parameters from the hypokalemic and hyperkalemic serum samples and observed lower bicarbonate concentrations, higher creatinine concentrations, and higher urea nitrogen concentrations in the hyperkalemic samples (p < 0.001 for each), without difference in glucose concentrations. Conclusion. We observed hyperkalemia 3 times as frequently as hypokalemia in our PD population. High-potassium diet, PD noncompliance, increased muscle mass, potassium shifts, and/or the daytime period without PD might contribute to hyperkalemia. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a worldwide public health concern characterised by a progressive alteration of renal function, and obesity, diabetes and hypertension are major risk factors. Oxidative stress is commonly observed in CKD patients resulting from an imbalance between overproduction of reactive oxygen species (ROS) and impairment of defense mechanisms. Therefore, strategies that alleviate oxidative stress may have major clinical implications towards improving vascular health and reducing the burden of CKD. Also, CKD worsens the quality of life of patients, therefore it is fundamental to implement new therapeutic strategies aimed at slowing down its progression. This interventional study is a randomised placebo-controlled clinical trial consisting at the daily oral supplementation with high dosing grape seed flour (GSF ≈ 1 g/kg) for experimental (n = 30) or starch for placebo (n = 10) to patients suffering from CKD of various stages and aetiologies. Blood and urine samples were collected at baseline and after a six-month-long supplementation period to follow up the disease evolution through the determination of renal function biomarkers, as well as antioxidant, anti-inflammatory and blood parameters. Supplementation with high dosing GSF was safe and well tolerated during the entire period of investigation. GSF clearly improved the main renal function biomarkers as GFR, proteinuria, blood pressure, oxidative stress and inflammation as well as the overall patient welfare as indicated by several blood parameters. Most importantly high dosing GSF specifically halted and even reversed the progression of diabetic nephropathy a major cause of CKD and end stage renal disease. [ABSTRACT FROM AUTHOR]

The inhibition of renin angiotensin system pathway has been largely documented to be effective in the control of cardiovascular events. The present study investigated the effect of angiotensin converting enzyme (ACE) inhibitor on fasting blood glucose level in hypertension induced by the inhibition of nitric oxide synthase (NOS) in male Wistar rats. Hypertension was induced by the inhibition of NOS using a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). The blockade of NOS resulted in an increase in blood pressure, ACE, angiotensin II and endothelin-1 levels, and a decrease in fasting blood glucose and nitric oxide (NO) levels. The hypertensive rats treated with ACE inhibitor (ramipril) recorded a decrease in blood pressure, ACE, angiotensin II, endothelin-1, NO and fasting blood glucose levels, and an increase in prostacyclin level. In conclusion, ACE inhibitor potentiated the hypoglycaemic effect of NOS inhibitor and this effect is independent of NO and pancreatic insulin release. [ABSTRACT FROM AUTHOR]

Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups (n=8) were given orally sulfasalazine (100mg/kg/day), low and high doses of OM (3.0 and 10.0mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and antiapoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis. [ABSTRACT FROM AUTHOR]

Context: Acute lung injury (ALI) is a serious heterogenous pulmonary disorder. Fraxinol was selected for this study since it is a simple coumarin compound, not previously investigated in ALI. Objectives: This study investigates the ALI therapeutic effect and mechanisms of fraxinol. Materials and methods: Male BALB/c mice were treated with fraxinol (20, 40, and 80mg/kg) following intranasal injection of lipopolysaccharide (LPS; 10 lg in 50lL). The mice in control group were intratracheally injected with 50 lL phosphate buffered saline (PBS). Raw264.7 cells were treated with fraxinol by 100 ng/mL LPS for 6 h, then treated by different concentrations of fraxinol (5, 10, and 25 lM) for 48 h. Cells in control group were treated with PBS. Results: Fraxinol with doses of 20, 40, and 80mg/kg significantly attenuated LPS-induced lung injury in mice (lung injury score, 10.4, 31.2, 50.3%). Fraxinol attenuated the apoptosis and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) activation induced by LPS (apoptosis, 18.3, 30.2, 55.6%; NLRP3, 30.0, 47.7, 63.6%). The anti-apoptosis and anti-inflammation effects of fraxinol were also confirmed in Raw264.7 cells (apoptosis, 38.8, 55.3, 68.9%; NLRP3, 20.6, 55.7, 73.9%). Discussion and conclusion: The anti-ALI effects of fraxinol maybe by equilibrating ACE-Ang II-AT1R and ACE2-Ang (1-7)-Mas axis and inhibiting NLRP3 inflammasome. Our research provides a candidate drug in the treatment of ALI. [ABSTRACT FROM AUTHOR]

We investigated the effect of dietary inclusions of Moringa seed (5% and 10%) on blood pressure, angiotensin-1 converting enzyme (ACE) activity, and gene expression, as well as redox status in hypertensive rats. Wistar strain albino rats were fed moringa seed-based diets for two weeks prior L-NAME (40 mg/kg/day, p.o.) administration for another ten days. Subsequently, the blood pressure was monitored. Furthermore, the kidney homogenates were assayed for ACE activity and gene expression, as well as oxidative stress markers. The increased (systolic = 297 ± 59.30 mmHg; diastolic= 242 ± 51.96 mmHg) blood pressure, arginase activity, and reduced nitric oxide level were significantly ameliorated in hypertensive rats treated with the seed. However, the elevated ACE activity was significantly reduced but not the upregulated ACE1 gene. Also, the reduced antioxidant enzyme activities were ameliorated with a significant downregulation in their regulator-Nrf2. Rutin (4.07 ± 0.02 mg/g) and quercitrin (4.06 ± 0.01 mg/g), among others, were found in the seed. This study suggests that moringa seed offers its antihypertensive properties by acting as an ACE inhibitor but not its gene modulator, and also modulates the antioxidant system through interaction with Nrf2. Moringa seed could act as an ACE inhibitor and not its gene modulator. [ABSTRACT FROM AUTHOR]

The objective of this study was to clinically and genetically characterize a pedigree with Liddle syndrome (LS). A LS pedigree comprising with one proband and seven family members was enrolled. The subjects' symptoms, laboratory results and genotypes were analyzed. Peripheral venous samples were collected from the subjects, and genomic DNA was extracted. DNA library construction and exome capture were performed on an Illumina HiSeq 4000 platform. The selected variant sites were validated using Sanger sequencing. The mutation effects were investigated using prediction tools. The proband and her paternal male family members had mild hypertension, hypokalemia and muscle weakness, including the absence of low renin and low aldosterone. Genetic analysis revealed that the proband carried a compound heterozygous mutation in SCNN1A, a novel heterozygous mutation, c.1130T > G (p.Ile377Ser) and a previously characterized polymorphism, c.1987A > G (p.Thr633Ala). The novel mutation site was inherited in an autosomal dominant manner and was predicted by in silico tools to exert a damaging effect. Alterations in the SCNN1A domain were also predicted by protein structure modeling. After six months of follow-up, treatment had significantly improved the patient's limb weakness and electrolyte levels. The novel mutation c.1130T > G of the SCNN1A gene was detected in the pedigree with LS. The clinical manifestations of the pedigree were described, which expand the phenotypic spectrum of LS. This result of this study also emphasizes the value of genetic testing for diagnosing LS. [ABSTRACT FROM AUTHOR]

Childhood trauma is an important risk factor for the onset and course of psychiatric disorders and particularly major depression. Recently, the renin-angiotensin-aldosterone system, one of the core stress hormone systems, has been demonstrated to be modified by childhood trauma. Childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ) in a community-dwelling sample (N = 2038). Plasma concentrations of renin and aldosterone were measured in subjects with childhood trauma (CT; N = 385) vs. subjects without this experience (NoCT; N = 1653). Multivariable linear regression models were calculated to assess the associations between CTQ, systolic and diastolic blood pressure, renin and aldosterone concentrations, and the ratio of aldosterone and systolic blood pressure (A/SBP). CT subjects demonstrated higher plasma aldosterone (A) concentrations, a lower systolic and diastolic blood pressure, and a higher A/SBP. In addition, both aldosterone concentrations, as well as A/SBP, correlated with the severity of childhood trauma. These findings could not be attributed to differences in concomitant medication. In conclusion, childhood trauma was associated with neurobiological markers, which may impact the risk for psychiatric disorders, primarily major depression. The altered A/SBP ratio points to a desensitisation of peripheral mineralocorticoid receptor function, which may be a target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: The renin–angiotensin system (RAS), which is important for controlling haemostasis in the body, can increase the development of essential hypertension (HTN). Various surveys have shown that ACE I/D polymorphism that influences ACE activity, a key component of RAS, has been known to be associated with the risk of HTN. The goal of this study was to investigate the correlation between ACE (I/D) polymorphism and HTN. Methods: Blood samples were obtained from 102 patients and 104 healthy individuals. The two groups were matched by age and sex. Informed consent was prepared for the study. The demographic data were collected using a questionnaire. White blood cells (WBCs) and then DNA were extracted from whole blood. After this, the PCR test was performed using specific primers. PCR products were examined using 1% agarose gel. Individuals with genotype II having a band of 490 bp, ID two band of 490 bp and 190 bp, and individuals with DD genotype, have a band in region 190 bp. Results: The average age of the patients was 52.7 ± 7.5 years. A significant difference was seen in the distribution of DD, II and I/D genotypes of ACE polymorphism between the essential hypertensive patients (44.1, 10.8, and 45.1%) and their ethnically matched healthy control (61.5, 3.8, and 24.6%, respectively). Our study showed an increased risk of disease in people with II genotype in comparison to ID and DD genotypes (0.46 (0.1–1.75) and 0.26 (0.05–0.94), respectively). Conclusions: The present study demonstrated that ACEI/D polymorphism is characterised with greater risk of essential HTN in the Lorestan province. II genotype increased the relative risk of essential HTN in the population. In the future, more investigations with more samples size are recommended for the better study of genetic factors in hypertensive patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify and quantify urinary Angiotensin-Converting-Enzyme (ACE) in hypertensive disorders of pregnancy. Urine samples were analyzed by Western blot. Patients were classified into: normotensive pregnancy (N); preeclampsia and superimposed preeclampsia (PE+SPE); and gestational hypertension (GH). Somatic ACE protein expression was higher in PE+SPE compared to N and GH. There was a positive correlation between ACE and urinary protein to creatinine ratio, systolic and diastolic blood pressures. These results indicate ACE overexpression in the urine of preeclamptic patients and suggest that it may be a new marker for the disease. [ABSTRACT FROM AUTHOR]

Hypertension and diabetes development had been characterized as idiopathic disorders tightly interconnected, and therefore it is essential to understand how the functionality of neurohormonal pathways are involved in both diseases. Hypertensive and diabetic patients have shown increased systolic blood pressure (SBP), oxidative stress, vascular hypertrophy, and remodeling. It is well established that the long-term consumption of red wine and/or polyphenol-stilbene causes cardioprotective and antihypertensive effects; however, some functions remain unrevealed. Downstream pathways such as reactive oxygen species (ROS), sympathoadrenal axis represented by β1-adrenoceptors, and renin–angiotensin system via angiotensin-II receptors critically contribute to hypertension development. This raised the issue of whether in vivo long-term red wine treatment can act as a modulator of these targets. We monitored SBP, glucose tolerance, oxidative stress, and cardiovascular function. Aortic and atrial tissues from normotensive-WKY, hypertensive-SHR, and diabetic-STZ animals, chronically exposed to red wine (3.715 ml/kg/v.o/day) or alcohol (12%) for 21-days, were used to measure contractile/relaxation responses by force transducers. Key findings: red wine, but not alcohol, prevented the increase of SBP and hyperglycemic peak. Additionally, was observed prevention of oxidative stress metabolites formation and an improvement in ROS scavenging antioxidant capacity of SHR. We also revealed that red wine intake enhances the endothelium-dependent relaxation, decreases the hypercontractile mediated by angiotensin-II in the aorta, and via β1-adrenoceptors in the atrium. The long-term consumption of red wine can improve oxidative stress and the functionality of angiotensin-II and β1-adrenoceptors, inspiring new pharmacologic and dietetic therapeutic approaches for the treatment of hypertension and diabetes. Abbreviation Acronyms and/or abbreviations: [Ca2+]cyt = Cytosolic Ca2+ Concentration; ACh = Acetylcholine; ANG II = Angiotensin II; AT1 = ANG II type 1 receptor; AUC = Area Under the Curve; Ca2+ = Calcium; Endo + = Endothelium Intact; Fen = Phenylephrine (1 μM); GTT = Glucose Tolerance Test; ISO = Isoprenaline (isoproterenol); KHN = Krebs-Henseleit Nutrient; LA = Left Atria; LH = Lipid Hydroperoxide; NO = Nitric Oxide; RA = Right Atria; RAS = Renin-Angiotensin System; ROS = Reactive Oxygen Species; SBP = Systolic Blood Pressure; SHR = Spontaneously Hypertensive Rats; STZ = Streptozotocin; WKY = Normotensive Wistar Kyoto Rats. [ABSTRACT FROM AUTHOR]

The effect of hypertension (HT) and antihypertensive therapies such as renin-angiotensin-aldosterone system (RAAS) blockers on the disease course in COVID-19 patients is controversial. The purpose of this study was to evaluate the effect of HT and antihypertensive therapies on the course of COVID-19 disease. The age, sex, comorbid diseases, and antihypertensive therapies of 132,790 patients with positive COVID-19 real-time transcriptase polymerase chain reaction (RT-PCR) tests in the Turkish Health Ministry National COVID-19 database between 11 March and 31 May 2020, were examined and analyzed. Forty-one percent of the 132,790 patients in this study (median age: 40, 47.3% female) were hospitalized for treatment, and 4.5% were followed-up in the intensive care unit (ICU). The most frequent comorbid disease, at 19.5%, was HT (n = 25,863). Mortality was determined in 4.9% of HT patients and 1.9% of non-HT patients (p <.001). HT, age, and male gender emerged as independent predictors of hospitalization and admission to the ICU, while HT was not a predictor of mortality. In addition, no adverse effect of any antihypertensive treatment, including RAAS inhibitors, on mortality was detected. Based on Turkish national data, HT is common in COVID-19 patients, but does not appear to be an independent predictor of mortality, and no adverse effect of RAAS inhibitors on COVID-19-related mortality was observed. [ABSTRACT FROM AUTHOR]

Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin–angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney–liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets. [ABSTRACT FROM AUTHOR]

Abnormal vasoconstriction, inflammation, and vascular remodeling can be promoted by angiotensin II (Ang II) in the renin–angiotensin system (RAS), leading to vascular dysfunction diseases such as hypertension and atherosclerosis. Researchers have recently focused on angiotensin I-converting enzyme inhibitory peptides (ACEIPs), that have desirable efficacy in vascular dysfunction therapy due to Ang II reduction by inhibiting ACE activity. Promising methods for the large-scale preparation of ACEIPs include selective enzymatic hydrolysis and microbial fermentation. Thus far, ACEIPs have been widely reported to be hydrolyzed from protein-rich sources, including animals, plants, and marine organisms, while many emerging microorganism-derived ACEIPs are theoretically biosynthesized through the nonribosomal peptide synthase (NRPS) pathway. Notably, vasodilatation, anti-inflammation, and vascular reconstruction reversal of ACEIPs are strongly correlated. However, the related molecular mechanisms underlying signal transduction regulation in vivo remain unclear. We provide a comprehensive update of the ACE-Ang II-G protein-coupled type 1 angiotensin receptor (AT1R) axis signaling and its functional significance for potential translation into therapeutic strategies, particularly targeting AT1R by ACEIPs, as well as specific related signaling pathways. Future studies are expected to verify the biosynthetic regulatory mechanism of ACEIPs via the NRPS pathway, the effect of gut microbiota metabolism on vascular dysfunction and rigorous studies of ACE-Ang II-AT1R signaling pathways mediated by ACEIPs in large animals and humans. [ABSTRACT FROM AUTHOR]

Studies reported conflicting results on the effect of renin-angiotensin-aldosterone system (RAAS) blocker use on acute kidney injury (AKI) in patients undergoing elective coronary angiography but association in elderly patients with ST-elevation myocardial infarction (STEMI) is not known. Also, there are limited data on the effect of inflammatory markers on AKI. We aimed to investigate the effects of RAAS blocker pretreatment and inflammatory markers on AKI in this population. A total of 471 patients were compared according to presence of RAAS blocker pretreatment at admission. Conventional and inverse probability weighed conditional logistic regression were used to determine independent predictors of AKI. Mean age of the study group was 75.4 ± 7.1 years and 29.1% of the patients were female. AKI was observed in 17.2% of the study population. Weighted conditional multivariable logistic regression analysis revealed that AKI was associated with baseline creatinine levels and C-reactive protein/albumin ratio (CAR) (OR 2.08, 95% CI = 1.13–3.82, p =.02 and OR 1.19, 95% CI = 1.01–1.41, p =.04, respectively). No significant association was found between RAAS blocker pretreatment and AKI. CAR and elevated baseline creatinine levels were independent predictors of AKI in this patient group. [ABSTRACT FROM AUTHOR]

Oestrogen deficiency is linked with pulmonary fibrosis. Additionally, it may lead to over-activation of the renin-angiotensin system (RAS), which worsens lung fibrosis. The present study aims to investigate the role of RAS on lung fibrosis associated with oestrogen deficiency in ovariectomised rats. Serum 17β-oestradiol (E2), arterial blood gases, plasma angiotensin II levels, lung tissue hydroxyproline content, and transforming growth factor beta 1 (TGF-β1) concentration, the mRNA expression of angiotensin type 1 receptor (AT1R), and angiotensin-converting enzyme (ACE1) were evaluated. Moreover, lung tissues were examined by histopathology and immunohistochemistry. Hydroxyproline content, TGF-β1 concentration, plasma angiotensin II, the relative mRNA expression of ACE1, and AT1R is found to increase in ovariectomised rats. The mentioned changes can be largely rescued by administration of RAS blockers. Oestrogen deficiency activates RAS, which consequently increases the expression of pro-fibrotic factors and stimulates the fibrotic cascade causing lung fibrosis. [ABSTRACT FROM AUTHOR]

The letter to the editor discusses a study on the factors affecting aldosterone levels in heart failure patients. The study found that patients with right-sided heart failure (RS-HF) had lower levels of aldosterone compared to other groups with heart failure. The authors suggest that this may be due to the use of diuretics and β2 agonists, which can inhibit aldosterone synthesis and cause hypokalemia. They also raise concerns about the lack of a clear definition for RS-HF and suggest that there may be overlap with heart failure with preserved ejection fraction (HFpEF). The authors recommend including information on medications that can affect aldosterone synthesis and clarifying the definition of RS-HF in future studies. [Extracted from the article]

Previously, we assessed that hypertension increases cataractogenesis. In the present study, we evaluated the effect of oral and topical administration of enalapril on two kidney one clip (2K1C)-induced hypertensive cataract model by evaluating the biochemical alteration of lenticular antioxidants, ionic content, ATPase activity, protein content and careful examination of the lenticular opacity. Animals were divided into normal and hypertensive animals. Hypertensive animals were divided into hypertensive control group (0.3% CMC), enalapril (oral) treatment group (20 mg/kg/day; p.o), and enalapril (topical) treatment group (0.1% w/v on the eye cornea) for a period of twelve weeks. During experimental study blood pressure, heart rate and morphology of the eyes were monitored biweekly. After twelve weeks, lenses were photographed and various catractogenic biochemical parameters were assessed. Enalapril (oral) treatment conserved the blood pressure (systolic and diastolic), restored the level of antioxidants, restored the lipid peroxidation marker, nitrite content, ionic content, ATPase function, protein content, and thus delayed the cataract formation. While, enalapril (topical) treatment exhibited anti-cataract effect without affecting the systolic and diastolic blood pressure that could be by restoring the antioxidant level, maintaining the ionic balance, balancing the protein levels, and by inhibiting the upregulated ocular renin angiotensin system. The overall results suggest that enalapril (topical) treatment showed conspicuous effect than enalapril (oral) treatment in adjourning the cataract formation. Based on the results, it may be concluded that upregulated ocular RAS by increasing oxidative stress and by misbalancing the lenticular ionic and protein content may lead to cataract formation in hypertensive condition. [ABSTRACT FROM AUTHOR]

Aliskiren (ALSK), being a direct renin inhibitor, is known for its additional benefit of renoprotection under several pathological conditions. On the other hand, Cisplatin (CP) is one of the most preferred chemotherapeutic agent; however, its clinical utility is limited owing to nephrotoxicity as its primary side effect. This study was aimed to investigate the protective role of ALSK against CP-induced nephrotoxicity in rats. Male Wistar rats were randomly divided into four groups of six animals each. They included vehicle treated normal control, CP (7.5 mg/kg), ALSK (25 mg/kg), and ALSK + CP treated groups. ALSK was orally administered for 2 weeks while CP was administered through the i.p. route on the 10th day to the respective groups. Blood and kidney samples were collected for the estimation of renal function, histology, the determination of oxidative stress, and the measurement of pro-inflammatory cytokines and markers of apoptosis. The results demonstrated that CP significantly elevated the levels of serum creatinine (Cr), blood urea nitrogen (BUN), and uric acid (UA) while it suppressed the renal markers of oxidative stress including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and increased malondialdehyde (MDA) content. In addition, CP up-regulated the markers of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α in the kidney and induced apoptosis by activating caspase cascade, which was observed as elevated levels of caspase-3 and −9. Two weeks of continuous treatment of ALSK 25 mg/kg significantly decreased the levels of serum Cr, BUN, UA and ameliorated histological damage in CP-treated animals. ALSK increased the antioxidant defense (increased renal GSH, SOD, and CAT levels while MDA content was suppressed) against CP. ALSK also significantly decreased the levels of IL-1β, IL-6, and TNF-α and prevented apoptosis by reversing the increased levels of caspase-3 and −9 by CP. Therefore, it may be concluded that ALSK has a protective role against CP-induced nephrotoxicity in rats. [ABSTRACT FROM AUTHOR]

The objective of this research is to evaluate the predictive capability of one-dimensional (1D), two-dimensional (2D), HEC-RAS models, for the computation of the travel time of a flood event and its flooding extent. The research was performed in the Grand River of Ohio, USA utilizing the same sets of geometric conditions such as LiDAR data integrated with field-surveyed cross-sections and the same set of flow conditions within the 1D, 2D, and coupled 1D/2D modeling features of HEC-RAS. The analysis suggested that the 2D model consistently outperformed 1D and coupled 1D/2D models. Furthermore, sensitivity analysis indicated that coupled 1D/2D and 1D models are relatively more sensitive than the 2D model to the inputs. The 1D model prediction for travel time was 20% more than the 2D model. Similarly, the inundation area from the 1D model was found to be slightly greater (4.1%) than that of the 2D model. [ABSTRACT FROM AUTHOR]

This study was conducted to explore the effect of renal denervation (RDN) on the renin–angiotensin–aldosterone system (RAAS) in spontaneously hypertensive rats (SHRs). Our experimental rats were randomly divided into the RDN group conducted by painting 10% phenol on the bilateral renal nerves (RDNX), the shamoperation group simply painting with saline (Sham), and the normotension control group (WKY) following all the animal blood and tissues of kidney, hypothalamus, and adrenal gland collected and examined 2 weeks after RDN operation. We found that the aldosterone (ALD) levels in serum and tissues all decreased in the RDNX group compared with the Sham group (p <.05). Meantime, the expression of angiotensin II type1 receptor (AT1R) mRNA also exhibited significantly reduced by 2.22-fold in the RDNX group compared to the Sham group identical to the expression of AT1R protein in the renal cortex and outer stripe of the outer medulla (OSOM) subjected to denervation surgery, which manifested the lower ATIR protein expression than the Sham group (p <.05). Besides, the expression of angiotensin II (Ang II) protein in the cortex , OSOM, and inner stripe of the outer medulla were all attenuated by RDN in comparison with the Sham group (p <.05). RDN reduced intrarenal RAAS and circulating RAAS to lower blood pressure and repair renal function. [ABSTRACT FROM AUTHOR]