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BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P

Hypertension is a multifactorial disease with stage-specific gene expression changes occurring in multiple organs over time. The temporal sequence and the extent of gene regulatory network changes occurring across organs during the development of hypertension remain unresolved. In this study, female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were used to analyze expression patterns of 96 genes spanning inflammatory, metabolic, sympathetic, fibrotic, and renin-angiotensin (RAS) pathways in five organs, at five time points from the onset to established hypertension. We analyzed this multi-dimensional dataset containing ~15,000 data points and developed a data-driven dynamic network model that accounts for gene regulatory influences within and across visceral organs and multiple brainstem autonomic control regions. We integrated the data from female SHR and WKY with published multiorgan gene expression data from male SHR and WKY. In female SHR, catecholaminergic processes in the adrenal gland showed the earliest gene expression changes prior to inflammation-related gene expression changes in the kidney and liver. Hypertension pathogenesis in male SHR instead manifested early as catecholaminergic gene expression changes in brainstem and kidney, followed by an upregulation of inflammation-related genes in liver. RAS-related gene expression from the kidney-liver-lung axis was downregulated and intra-adrenal RAS was upregulated in female SHR, whereas the opposite pattern of gene regulation was observed in male SHR. We identified disease-specific and sex-specific differences in regulatory interactions within and across organs. The inferred multi-organ network model suggests a diminished influence of central autonomic neural circuits over multi-organ gene expression changes in female SHR. Our results point to the gene regulatory influence of the adrenal gland on spleen in female SHR, as compared to brainstem influence on kidney in male SHR. Our integrated molecular profiling and network modeling identified a stage-specific, sex-dependent, multi-organ cascade of gene regulation during the development of hypertension. [ABSTRACT FROM AUTHOR]

Background: The exact pathogenesis of Huntington's disease (HD) remains unclear. However, mitochondrial dysfunction and oxidative stress are supposed to play a significant role. The objective of this study was to examine the possible neuroprotective effect of Lisinopril (Lisino) in a 3-nitropropionic acid-produced HD in rats. Methods: Sixty-four rats were divided into four groups (16/group): Group (1): Normal control group, Group (2): Lisinopril control group, Group (3): 3-NP non-treated group, and Group (4): (3-NP + Lisinopril) group. Behavior assessments (open field test, rotarod test, grip strength test) were performed along with different histological and biochemical parameters. Results: Lisinopril upregulated the expression of the ACE2/Ang1-7/MAS receptor (MasR) axis of RAS, which triggered the PI3K/Akt pathway and prompted the CREB/BDNF neurogenesis signal. Furthermore, Lisinopril remarkably downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6), decreased apoptotic markers (p53, BAX/Bcl2 ratio, Cyt-c and caspase-3) and upgraded the mitochondrial TFAM content and SDH activity along with restoration of the redox mechanism by recovering SOD, catalase, GSH and Nrf2. Conclusion: Notably, the outcomes of this study disclosed that Lisinopril could be a future neuroprotective therapeutic candidate against HD. Research highlights: Lisinopril alleviated the mitochondrial dysfunction and restored redox balance via Nrf2/TFAM signaling. Lisinopril downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6). Lisinopril upregulated the expression of ACE2/Ang1-7/MAS receptor axis of RAS. Lisinopril activated PI3K/Akt/CREB pathway and evoked the neurogenesis via its downstream product BDNF. Lisinopril could be a future neuroprotective treatment against Huntington disease. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio‐renal complications and guide treatment interventions in people with diabetes.We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon‐like peptide‐1 (GLP‐1) receptor agonists.Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney‐derived anti‐ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT‐2 inhibitors and GLP‐1 receptor agonists all influence pathways involved in vascular ageing.A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio‐renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the expression of ACE and ACE2 in the placenta and white adipose tissue in lean and obese women, and correlated their levels with anthropometric, clinical, and laboratory parameters, and tissue count of inflammatory cells. Methods: A cross-sectional analytical study was performed with 49 pregnant women and their respective newborns. Samples of placenta and adipose tissue were used for measuring mRNA expression for ACE and ACE2 through qRT-PCR. Inflammatory cell counting was performed through conventional microscopy. Results: An increase in ACE expression and a decrease in ACE2 were observed in the placenta and adipose tissue of women with obesity. ACE2 levels showed a negative correlation with pre-pregnancy BMI and total cholesterol. Conclusion: Maternal obesity can modulate the expression of RAS components in the placenta and white adipose tissue, with ACE2 correlated with pre-pregnancy BMI and total cholesterol. [ABSTRACT FROM AUTHOR]

Ascites is the most common complication in patients with decompensated cirrhosis. This condition results in a severely impaired quality of life, excessive healthcare use, recurrent hospitalizations and significant morbidity and mortality. While loop diuretics and mineralocorticoid receptor antagonists are commonly employed for symptom relief, our understanding of their impact on survival remains limited. A comprehensive understanding of the underlying pathophysiological mechanism of ascites is crucial for its optimal management. The renin-angiotensin-aldosterone system (RAAS) is increasingly believed to play a pivotal role in the formation of cirrhotic ascites, as RAAS overactivation leads to a reduction in urine sodium excretion then a decrease in the ability of the kidneys to excrete water. In this review, the authors provide an overview of the pathogenesis of cirrhotic ascites, the challenges associated with current pharmacologic treatments, and the previous attempts to modulate the RAAS, followed by a description of some emerging targeted RAAS agents with the potential to be used to treat ascites. [ABSTRACT FROM AUTHOR]

The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health, with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue, which orchestrates energy, lipids, and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can, in turn, influence mineralocorticoid system activity by harboring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, resulting in further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide and thought to be a benign disease. Recent literature review would suggest otherwise, with outcomes remaining generally poor. Few patients do not progress to kidney failure in their lifetime even in population groups previously thought to be low risk. The previously established treatment approach predominantly focuses on supportive care through renin–angiotensin–aldosterone system inhibition and steroid‐based immunosuppression in selected cases. However, recent advances in the understanding of the pathogenic mechanisms underlying this disease process have allowed for the development of new target therapies. This brief review provides an overview of improved understanding of IgA nephropathy and novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Chihuahua represents an increasingly widespread breed predisposed to cardiac disease. N-terminal pro-B-type natriuretic peptide (NT-proBNP) might be a useful point-of-care biomarker for dogs suspected of having heart disease, but breed differences have been reported. The urinary aldosterone-to-creatinine ratio (UAldo: C) appears to be a good indicator of renin-angiotensin-aldosterone system activity in dogs, but Chihuahuas showed significantly higher UAldo: C than other breeds. The objective of this study was to assess preliminary breed-specific reference intervals for NT-proBNP and UAldo: C in healthy Chihuahuas and evaluate sex differences in these parameters. Results: Forty-three healthy Chihuahuas dogs were enrolled. The median NT-proBNP was 347 (125–515) pmol/L, and the median UAldo: C was 2.59 (1.57–4.61) µg/g. The NT-proBNP reference interval was 125 (90% CI 125–125) – 2121.4 (90% CI 941.6–2248) pmol/L. 91% of the Chihuahuas were below the nonbreed-specific cut-off (900 pmol/L). The UAldo: C reference interval was 0.6 (90% CI 0.5–0.9) – 16.8 (90% CI 10.9–27.4) µg/g. No significant sex differences in NT-proBNP or UAldo: C were found. Conclusions: The median value, interindividual coefficient of variation and reference interval of NT-proBNP were in line with those reported for other small breeds. In contrast to previous studies, no sex differences in NT-proBNP were detected. As previously suggested, Chihuahuas seem to be characterized by higher values of UAldo: C than other breeds. [ABSTRACT FROM AUTHOR]

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm–Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress. [ABSTRACT FROM AUTHOR]

Background: Although the pathogenesis of essential hypertension is not clear, a large number of studies have shown that oxidative stress plays an important role in the occurrence and development of hypertension and target organ damage. Purpose: This paper systematically summarizes the relationship between oxidative stress and hypertension, and explores the potential mechanisms of Chinese herbal medicine (CHM) in the regulation of oxidative stress in hypertension, aiming to establish a scientific basis for the treatment of hypertension with CHM. Methods: To review the efficacy and mechanism by which CHM treat hypertension through targeting oxidative stress, data were searched from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the Chinese National Knowledge Infrastructure, the VIP Information Database, the Chinese Biomedical Literature Database, and the Wanfang Database from their inception up to January 2024. NPs were classified and summarized by their mechanisms of action. Results: In hypertension, the oxidative stress pathway of the body is abnormally activated, and the antioxidant system is inhibited, leading to the imbalance between the oxidative and antioxidative capacity. Meanwhile, excessive production of reactive oxygen species can lead to endothelial damage and vascular dysfunction, resulting in inflammation and immune response, thereby promoting the development of hypertension and damaging the heart, brain, kidneys, blood vessels, and other target organs. Numerous studies suggested that inhibiting oxidative stress may be the potential therapeutic target for hypertension. In recent years, the clinical advantages of traditional Chinese medicine (TCM) in the treatment of hypertension have gradually attracted attention. TCM, including active ingredients of CHM, single Chinese herb, TCM classic formula and traditional Chinese patent medicine, can not only reduce blood pressure, improve clinical symptoms, but also improve oxidative stress, thus extensively affect vascular endothelium, renin–angiotensin–aldosterone system, sympathetic nervous system, target organ damage, as well as insulin resistance, hyperlipidemia, hyperhomocysteinemia and other pathological mechanisms and hypertension related risk factors. Conclusions: CHM display a beneficial multi-target, multi-component, overall and comprehensive regulation characteristics, and have potential value for clinical application in the treatment of hypertension by regulating the level of oxidative stress. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions This study aimed to explore the effect of discontinuation of long‐term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study.An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re‐examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin‐creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow‐up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium.No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI −12, 55; p = 0.28) nor the placebo (5%; 95% CI −13, 26; p = 0.63) group at follow‐up. No difference in UACR between the groups was observed at follow‐up (relative difference in geometric mean: 11%, 95% CI −26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05).UACR did not change after discontinuation of long‐term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys. [ABSTRACT FROM AUTHOR]

Background: Age-related reproductive aging is a natural and irreversible physiological process, and delaying childbearing is increasingly common all over the world. Transplantation of mesenchymal stem cells (MSCs) is considered a new and effective therapy to restore ovarian function, but the relevant mechanisms remain unclear. Recently, it has been found that there is a local Renin–angiotensin system (RAS) in human ovary and it plays a key role. Methods: After collecting follicular fluid from women who received oocyte retrieval for pure male factor infertility, the level of RAS components in it were detected, and the correlation analysis by linear regression. Then, the in vivo experiments on female C57BL/6 mice were designed to measure ovarian function, and the transcription and translation levels of RAS pathway were detected by molecular biology methods. Moreover, the role of RAS in regulating inflammation and oxidative stress in the co-culture system were explored in in vitro experiments on KGN cells. Results: First, a total of 139 samples of analyzable follicular fluid were obtained. The local RAS of ovary, which is independent of systemic RAS (P > 0.05), is affected by age (Pearson r < 0, P < 0.05) and related to ovarian function, inflammation, oxidative stress indexes and assisted reproduction laboratory outcomes (P < 0.05). Next, the ovary/body weight of aging mice decreased significantly and serum sex hormones levels changed significantly (P < 0.01). The number of functional follicles decreased, while the atresia follicles increased (P < 0.05). After MSCs transplantation, all the above measures have been partially recovered (P < 0.05). Although several RAS components in aging ovary changed, MSCs only improved the expression level of AT1R (P < 0.05). Furthermore, the secretion ability and mitochondrial membrane potential of aging KGN cells decreased, while the intracellular ROS level and the aging cells ratio increased (P < 0.01). All the above measures have been partially recovered when co-cultured with MSCs (P < 0.05). After Ang(1–7) were added into the co-culture system, the above have been more significantly restored compared with Ang II (P < 0.05). Nevertheless, there was no statistical difference in estradiol level no matter which one was added (P > 0.05). Conclusions: Together, our findings indicate that a novel possible mechanism to explain how stem cells restore age-related ovarian functional decline. [ABSTRACT FROM AUTHOR]

Since December 2019, coronavirus disease 2019 (COVID-19) has been spreading worldwide with devastating immediate or long-term effects on people's health. Although the lungs are the primary organ affected by COVID-19, individuals infected with SARS-CoV-2 also develop systemic lesions involving multiple organs throughout the body, such as the cardiovascular system. Emerging evidence reveals that COVID-19 could generate myocardial fibrosis, termed "COVID-19-associated myocardial fibrosis." It can result from the activation of fibroblasts via the renin-angiotensin-aldosterone system (RAAS), transforming growth factor-ß1 (TGF-ß1), microRNAs, and other pathways, and can also occur in other cellular interactions with SARS-CoV-2, such as immunocytes, endothelial cells. Nonetheless, to gain a more profound insight into the natural progression of COVID-19-related myocardial fibrosis, additional investigations are necessary. This review delves into the underlying mechanisms contributing to COVID-19-associated myocardial fibrosis while also examining the antifibrotic potential of current COVID-19 treatments, thereby offering guidance for future clinical trials of these medications. Ultimately, we propose future research directions for COVID-19-associated myocardial fibrosis in the post-COVID-19 era, such as artificial intelligence (AI) telemedicine. We also recommend that relevant tests be added to the follow-up of COVID-19 patients to detect myocardial fibrosis promptly. [ABSTRACT FROM AUTHOR]

A strict correlation among proximal tubule epithelial cell dysfunction, proteinuria, and modulation of the Renin-Angiotensin System and Kalikrein-Kinin System are crucial factors in the pathogenesis of Acute Kidney Injury (AKI). In this study, we investigated the potential protective effect of preconditioning by moderate-intensity aerobic exercise on gentamicin-induced AKI. Male Wistar rats were submitted to a moderate-intensity treadmill exercise protocol for 8 weeks, and then injected with 80 mg/kg/day s.c. gentamicin for 5 consecutive days. Four groups were generated: 1) NT+SAL (control); 2) NT+AKI (non-trained with AKI); 3) T+SAL (trained); and 4) T+AKI (trained with AKI). The NT+AKI group presented: 1) impairment in glomerular function parameters; 2) increased fractional excretion of Na+ , K+ , and water; 4) proteinuria and increased urinary γ-glutamyl transferase activity (a marker of tubular injury) accompanied by acute tubular necrosis; 5) an increased renal angiotensin-converting enzyme and bradykinin B1 receptor mRNA expression. Interestingly, the preconditioning by moderate-intensity aerobic exercise attenuated all alterations observed in gentamicin-induced AKI (T+AKI group). Taken together, our results show that the preconditioning by moderate-intensity aerobic exercise ameliorates the development of gentamicin-induced AKI. Our findings help to expand the current knowledge regarding the effect of physical exercise on kidneys during physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Heart failure is a significant health issue in developed countries, often stemming from conditions like hypertension, which imposes a pressure overload on the heart. Despite various treatment strategies for heart failure, many lack long-term effectiveness. A critical aspect of cardiac disease is the remodeling of the heart, where compensatory changes in the extracellular matrix exacerbate disease progression. This review explores the processes and changes occurring in the pressure-overloaded heart with respect to the extracellular matrix. It further summarizes current treatment strategies, and then focuses on novel treatment targets for maladaptive cardiac remodeling, derived from transverse aortic constriction-induced pressure overload animal models. [ABSTRACT FROM AUTHOR]

Introduction: Kuwait has a large expatriate community who experience both restricted access to public health services and lower income than Kuwaiti citizens. Given these conditions, we examined differences in characteristics and management of chronic kidney disease (CKD) between Kuwaitis and expatriates. Methods: Clinical and laboratory data for adult CKD Stages 3–5 not on dialysis (CKD 3–5 ND) patients with native kidneys attending nephrology clinics in all Ministry of Health hospitals collected from January 1, 2022, to December 31, 2022. Cohort was then divided into Kuwaiti patients and expatriates patients for comparison. Results: We collected data from 2,610 patients (eGFR: 30.8 ml/min/1.73m2; age: 62.6 years; males: 56.7%; Kuwaitis: 62.1%). Kuwaitis were older (63.94 vs. 60.3 years, p < 0.001), with lower mean eGFR (30.4 vs. 31.5 ml/min/1.73m2, p = 0.052) than non-Kuwaitis, however, Kuwaitis had lower mean blood pressure (137.2/76.5 vs. 139.1/78.9 mmHg, p = 0.006), lower HbA1c in diabetics (7.59 vs. 7.82%, p = 0.010), and better lipid profile despite higher body mass indexes (29.6 vs. 28.9 kg/m2, p = 0.002). Both groups had high diabetes mellitus and hypertension rates. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were used in only 22.6% and renin-angiotensin-aldosterone system inhibitors (RAASi) in only 46.2%. Conclusion: CKD 3–5 ND is caused by diabetes mellitus in 56.6% of cases, and the majority have hypertension. In our study, non-Kuwaitis had higher eGFR; however, restricted public healthcare access and lower income can lead to an unhealthy diet and suboptimal care, which may cause higher blood pressure, higher HbA1c, and a higher dyslipidemia rate. RAASi and SGLT2i utilization must increase to combat CKD, and antihypertensive selection must improve. [ABSTRACT FROM AUTHOR]

Background: Renin-angiotensin-aldosterone system (RAAS) inhibitors appear to benefit bone tissue in antihypertensive treatment. However, the association between RAAS inhibitors and bone metabolism was inconsistent. Methods and study design: Based on the study of Risk Evaluation of Cancers in Chinese Diabetic Individuals(REACTION) conducted in 2011, We followed 6,252 Lanzhou residents aged 40–75 years from 2014 to 2016. Finally, 1,625 hypertension cases with complete data were included in the analysis. The study subjects were divided into four groups according to the type of antihypertensive drugs. We employed logistic or multivariate Cox proportional hazards regression to estimate the association between different antihypertensive drug use and osteoporosis, the risk of fracture, and the change in bone mineral density (BMD) level. The association of osteoporosis or the fracture risk by cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. Results: The cross-sectional study showed that there was no significant association between baseline antihypertensive drugs (angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)) use and osteoporosis and fracture. During a mean follow-up of 3.4 years in the longitudinal study, there were 478 new osteoporosis cases and 76 fractures. Compared with patients without antihypertensive drug use, the hazard ratios (HRs) [95% confidence interval (CI)] for the risk of osteoporosis were 1.005(0.651,1.552) and 1.077(0.793,1.462) in ACEI or ARB use (p > 0.05). ACEI or ARB use was also not significantly associated with fracture risk (HR 1.102(0.326,3.726), 0.735(0.251,2.148), p > 0.05). Further analysis showed that the use of ACEI (HR 1.078(0.146,7.950)) or ARB (HR 1.169(0.347,3.939)) was not significantly associated with the improvement of osteoporosis (p > 0.05). In addition, the duration of RAAS inhibitors used showed no apparent correlation with the risk of osteoporosis (≤ 3 years: HR 0.872 (0.516, 1.474), > 3 years: HR 1.151 (0.574, 2.308)), nor with the improvement of osteoporosis and the risk of fracture. Meanwhile, the association mentioned above did not change compared to different RAAS inhibitors. Conclusions: The use of RAAS inhibitors, including ACEIs and ARBs, was not significantly associated with osteoporosis, risk of fracture, or BMD change. [ABSTRACT FROM AUTHOR]

Introduction: Holistic Approach in Lowering and Tracking Chronic Kidney Disease (HALT-CKD) is a nationwide programme that was introduced in 2017 to combat CKD in Singapore. This study aims to evaluate outcomes of the HALT-CKD programme and identify factors influencing disease progression among early CKD patients. Method: We conducted a retrospective cohort study involving adult patients aged 21 to 80 with CKD stages G1-G3A, recruited from 5 Singapore polyclinics between 2017 and 2018. The primary outcome--time to progression to advanced CKD (G3B-G5)--was tracked until March 2023, based on patients' last known serum creatinine levels. Descriptive statistics and Cox regression were used. Patients who followed up with other institutions, were deceased or defaulted without developing (or experiencing) the outcome were censored. Results: We studied 3800 patients (mean age: 61.9 years) for a median of 4.7 years. Among them, 12.6% developed advanced CKD despite statistically significant improvements in HbA1c, blood pressure and albuminuria levels. Increasing age, female sex, clinic, baseline creatinine, diastolic blood pressure and HbA1c significantly shortened time to CKD progression. Macro-albuminuria at baseline (hazard ratio [HR] 1.77, 95% confidence interval [CI] 1.19-2.61) and at analysis (HR 2.22, 95% CI 1.55-3.19) significantly accelerated advanced CKD progression. Patients who had their angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) dose reduced or discontinued progressed to advanced CKD earlier (HR 1.92, 95% CI 1.50-2.45). Counselling and sodium-glucose cotransporter-2 inhibitor (SGLT2i) use did not significantly delay CKD progression. Conclusion: Maintaining optimal ACEi/ARB dosage is essential to delay CKD progression. Premature cessation or reduction of this dosage should be discouraged. Further research on counselling and SGLT2i use in early CKD is needed to address the growing burden of CKD. [ABSTRACT FROM AUTHOR]

Simple Summary: Traditionally, models of neurodegenerative diseases focus on changes within the central nervous system. However, growing evidence indicates there are prominent interactions between the cardiovascular system and neurodegenerative diseases. In this review, we discuss cardiovascular impairments in models of neurodegeneration, neurological impairments in models of cardiovascular disease, and what occurs when the two are combined as a first step toward improving our understanding of the pathophysiology of neurodegenerative diseases. Neurological diseases, including neurodegenerative diseases (NDDs), are the primary cause of disability worldwide and the second leading cause of death. The chronic nature of these conditions and the lack of disease-modifying therapies highlight the urgent need for developing effective therapies. To accomplish this, effective models of NDDs are required to increase our understanding of underlying pathophysiology and for evaluating treatment efficacy. Traditionally, models of NDDs have focused on the central nervous system (CNS). However, evidence points to a relationship between systemic factors and the development of NDDs. Cardiovascular disease and related risk factors have been shown to modify the cerebral vasculature and the risk of developing Alzheimer's disease. These findings, combined with reports of changes to vascular density and blood–brain barrier integrity in other NDDs, such as Huntington's disease and Parkinson's disease, suggest that cardiovascular health may be predictive of brain function. To evaluate this, we explore evidence for disruptions to the circulatory system in murine models of NDDs, evidence of disruptions to the CNS in cardiovascular disease models and summarize models combining cardiovascular disruption with models of NDDs. In this study, we aim to increase our understanding of cardiovascular disease and neurodegeneration interactions across multiple disease states and evaluate the utility of combining model systems. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling. [ABSTRACT FROM AUTHOR]

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

Rationale: Exercise attenuates addictive behavior; however, little is known about the contribution of exercise duration to this positive effect. The Renin Angiotensin System (RAS) has been implicated both in addictive responses and in the beneficial effects of exercise; though, its role in the advantageous effects of exercise on toluene-induced addictive responses has not been explored. Objectives: To evaluate the impact of different exercise regimens in mitigating the expression of toluene-induced locomotor sensitization and to analyze changes in RAS elements' expression at the mesocorticolimbic system after repeated toluene exposure and following voluntary wheel running in toluene-sensitized animals. Methods: Toluene-induced addictive-like response was evaluated with a locomotor sensitization model in mice. Toluene-sensitized animals had access to running wheels 1, 2, 4 or 24 h/day for 4 weeks; thereafter, locomotor sensitization expression was evaluated after a toluene challenge. RAS elements (ACE and ACE2 enzymes; AT1, AT2 and Mas receptors) expression was determined by Western blot in the VTA, NAc and PFCx of toluene-sensitized mice with and without exercise. Results: Individual differences in toluene-induced locomotor sensitization development were observed. Access to wheel running 1 and 2 h/day reduced but 4 and 24 h/day completely blocked locomotor sensitization expression. Repeated toluene exposure changed RAS elements' expression in the VTA, NAc and PFCx, while exercise mainly modified ACE and AT1 in air-exposed and toluene-sensitized mice. Conclusions: Inhalant-exposed animals show different sensitization phenotypes. Exercise duration determined its efficacy to attenuate the addictive-like response. Toluene exposure and exercise each modified RAS, the latter also modifying toluene-induced changes. [ABSTRACT FROM AUTHOR]

Background: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case–control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. Methods: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000–2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic–severe sepsis associations. Results: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin–angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. Conclusion: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin-aldosterone system (RAAS) is responsible for a multitude of physiological functions, including immunological effects such as promotion of TGF-β and upregulation of IL-6 and IL-8 which are also implicated in the development of chronic lung allograft dysfunction (CLAD). Blockade of the RAAS pathway in pre-clinical models has demonstrated a decrease in these cytokines and pulmonary neutrophil recruitment. Objective: This study sought to evaluate whether use of RAAS inhibitor (RAASi) in lung transplant recipients impacted CLAD-free survival. Methods: In this retrospective, single-center study, 35 lung transplant recipients who received a RAASi post-transplant were compared to 70 lung transplant recipients not exposed to a RAASi and were followed for up to 5 years post-transplant. Results: The incidence of CLAD did not differ based on RAASi treatment (34.3% in RAASi vs 38.6%, P -value.668). This was confirmed with a multivariable Cox proportional hazards model with RAASi initiation as a time-varying covariate (RAASi hazard ratio of 1.01, P -value.986). Incidence of hyperkalemia and acute kidney injury were low in the RAASi group. Conclusions: This study demonstrated no association between post-transplant RAASi use and decreased risk of CLAD development. RAASi were also well tolerated in this patient population. [ABSTRACT FROM AUTHOR]

Infants with a congenital anomaly of the kidney and urinary tract sometimes present with hyponatremia, hyperkalemia, and metabolic acidosis due to under-responsiveness to aldosterone, hereafter referred to as secondary pseudo-hypoaldosteronism. The purpose of this report is to investigate pseudo-hypoaldosteronism in infant urinary tract infection. A systematic review was conducted following PRISMA guidelines after PROSPERO (CRD42022364210) registration. The National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar without limitations were used. Inclusion criteria involved pediatric cases with documented overt pseudo-hypoaldosteronism linked to urinary tract infection. Data extraction included demographics, clinical features, laboratory parameters, management, and course. Fifty-seven reports were selected, detailing 124 cases: 95 boys and 29 girls, 10 months or less of age (80% of cases were 4 months or less of age). The cases exhibited hyponatremia, hyperkalemia, acidosis, and activated renin-angiotensin II-aldosterone system. An impaired kidney function was found in approximately every third case. Management included antibiotics, fluids, and, occasionally, emergency treatment of hyperkalemia, hyponatremia, or acidosis. The recovery time averaged 1 week for electrolyte, acid–base imbalance, and kidney function. Notably, anomalies of the kidney and urinary tract were identified in 105 (85%) cases. Conclusions:This review expands the understanding of overt transient pseudo-hypoaldosteronism complicating urinary tract infection. Management involves antimicrobials, fluid replacement, and consideration of electrolyte imbalances. Raising awareness of this condition within pediatric hospitalists is desirable. What is Known: • Infants affected by a congenital anomaly of the kidney and urinary tract may present with clinical and laboratory features resembling primary pseudo-hypoaldosteronism. • Identical features occasionally occur in infant urinary tract infection. What is New: • Most cases of secondary pseudo-hypoaldosteronism associated with a urinary tract infection are concurrently affected by a congenital anomaly of the kidney and urinary tract. • Treatment with antibiotics and parenteral fluids typically results in the normalization of sodium, potassium, bicarbonate, and creatinine within approximately 1 week. [ABSTRACT FROM AUTHOR]

Infantile hemangioma (IH), the most common vascular tumor in pediatrics, is thought to arise from aberrant stem cell responses to stimuli such as hypoxia. This review explores the diverse manifestations, complications, and management strategies for IH, emphasizing the importance of a multidisciplinary approach. The epidemiology and risk factors associated with IH, including connections to prematurity, low birth weight, and family background, are discussed. The intricate pathogenesis involving hemangioma stem cells, KIAA1429, hypoxia, and the renin-angiotensin system is examined. The natural history and clinical features, as well as extracutaneous involvements such as hepatic IH, PHACES syndrome, and LUMBAR syndrome, are detailed. Complications such as ulceration, functional impairment, hypothyroidism, and cosmetic concerns are highlighted. The differential diagnosis and diagnostic modalities, including colorimeters, high-frequency ultrasonography, and imaging techniques, are discussed. Management approaches, including the use of propranolol, atenolol, corticosteroids, alternative systemic treatments, topical therapy, laser therapy, and surgery, are comprehensively reviewed. The evolving landscape of IH management is underscored, with ongoing research exploring alternative treatments and individualized approaches based on IH characteristics. [ABSTRACT FROM AUTHOR]

High-level spinal cord injury (SCI) often results in cardiovascular dysfunction, especially the development of autonomic dysreflexia. This disorder, characterized as an episode of hypertension accompanied by bradycardia in response to visceral or somatic stimuli, causes substantial discomfort and potentially life-threatening symptoms. The neural mechanisms underlying this dysautonomia include a loss of supraspinal control to spinal sympathetic neurons, maladaptive plasticity of sensory inputs and propriospinal interneurons, and excessive discharge of sympathetic preganglionic neurons. While neural control of cardiovascular function is largely disrupted after SCI, the renin-angiotensin system (RAS), which mediates blood pressure through hormonal mechanisms, is up-regulated after injury. Whether the RAS engages in autonomic dysreflexia, however, is still controversial. Regarding therapeutics, transplantation of embryonic presympathetic neurons, collected from the brainstem or more specific raphe regions, into the injured spinal cord may reestablish supraspinal regulation of sympathetic activity for cardiovascular improvement. This treatment reduces the occurrence of spontaneous autonomic dysreflexia and the severity of artificially triggered dysreflexic responses in rodent SCI models. Though transplanting early-stage neurons improves neural regulation of blood pressure, hormonal regulation remains high and baroreflex dysfunction persists. Therefore, cell transplantation combined with selected RAS inhibition may enhance neuroendocrine homeostasis for cardiovascular recovery after SCI. [ABSTRACT FROM AUTHOR]

Hypertensive renal damage (HRD) is a major cause of end-stage renal disease. Among the causes of end-stage renal disease, HRD accounts for nearly 34% of the total number of cases. Antihypertensive treatment is primarily drug-based, but therapeutic efficacy is less effective and can have serious side effects. Chinese medicine (CM) has significant advantages in the treatment of HRD. CM is rich in various active ingredients and has the property of targeting multiple targets and channels. Therefore, the regulatory network of CM on disease is complex. A large number of CM have been employed to treat HRD, either as single applications or as part of compound formulations. The key possible mechanisms of CM for HRD include regulation of the renin-angiotensin-aldosterone system, antioxidation, anti-inflammation, rescue of endothelial function, regulation of vasoactive substance secretion and obesity-related factors, etc. This review summarized and discussed the recent advance in the basic research mechanisms of CM interventions for HRD and pointed out the challenges and future prospects. [ABSTRACT FROM AUTHOR]

Activation of the renin-angiotensin system (RAS) triggers oxidative stress and an inflammatory response in the hypothalamic paraventricular nucleus (PVN), in turn increasing the sympathetic hyperactivity that is a major cause of hypertension. Pyridostigmine has cardioprotective effects by suppressing the RAS of myocardial tissue. However, whether pyridostigmine attenuates hypertension by inhibiting the RAS of the PVN remains unclear. We thus investigated the effect and mechanism of pyridostigmine on two-kidney one-clip (2K1C)-induced hypertension. 2K1C rats received pyridostigmine, or not, for 8 weeks. Cardiovascular function, hemodynamic parameters, and autonomic activity were measured. The PVN levels of pro-/anti-inflammatory cytokines, oxidative stress, and RAS signaling molecules were evaluated. Our results showed that hypertension was accompanied by cardiovascular dysfunction and an autonomic imbalance characterized by enhanced sympathetic but diminished vagal activity. The PVN levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), NOX-2, and malondialdehyde (MDA) increased; those of IL-10 and superoxide dismutase (SOD) decreased. Moreover, the RAS signaling pathway was activated, as evidenced by increased levels of the angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the Ang II type 1 receptor (AT1R) and a decreased AT2R level. Pyridostigmine lowered blood pressure and improved cardiovascular function, associated with restoration of the autonomic balance. Meanwhile, pyridostigmine decreased PVN IL-6, TNF-α, ROS, NOX-2, and MDA levels and increased IL-10 and SOD levels. Additionally, pyridostigmine suppressed PVN ACE, Ang II, and AT1R levels and increased AT2R expression. Pyridostigmine attenuated hypertension by inhibiting PVN oxidative stress and inflammation induced by the RAS. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion 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.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.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.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. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is a continuation strategy of renin-angiotensin system inhibitors before major noncardiac surgery associated with better postoperative outcomes than discontinuation? Findings: In this multicenter randomized clinical trial that included 2222 patients, the rate of all-cause mortality and major postoperative complications was 22% in the discontinuation group and 22% in the continuation group (risk ratio, 1.02). Meaning: In patients undergoing major noncardiac surgery and treated long-term with renin-angiotensin system inhibitors, a continuation strategy of the medication was associated with a similar rate of all-cause mortality and major postoperative complications compared with a discontinuation strategy. Importance: Before surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines. Objective: To evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery. Design, Setting, and Participants: Randomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France. Intervention: Patients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery. Results: Of the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P =.85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes. Conclusions and Relevance: Among patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT03374449 This randomized clinical trial compares the effect of continued use of renin-angiotensin system inhibitors (RASIs) vs discontinued use of RASIs before major noncardiac surgery on postoperative complications. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2), a crucial element of the renin-angiotensin system (RAS), metabolizes angiotensin II into Ang (1–7), which then combines with the Mas receptor (MasR) to fulfill its protective role in various diseases. Nevertheless, the involvement of ACE2 in sepsis-induced cardiomyopathy (SIC) is still unexplored. In this study, our results revealed that CLP surgery dramatically impaired cardiac function accompanied with disruption of the balance between ACE2-Ang (1–7) and ACE-Ang II axis in septic heart tissues. Moreover, ACE2 knockin markedly alleviated sepsis induced RAS disorder, cardiac dysfunction and improved survival rate in mice, while ACE2 knockout significantly exacerbates these outcomes. Adoptive transfer of bone marrow cells and in vitro experiments showed the positive role of myeloid ACE2 by mitigating oxidative stress, inflammatory response, macrophage polarization and cardiomyocyte apoptosis by blocking NF-κB and STAT1 signals. However, the beneficial impacts were nullified by MasR antagonist A779. Collectively, these findings showed that ACE2 alleviated SIC by inhibiting M1 macrophage via activating the Ang (1–7)-MasR axis, highlight that ACE2 might be a promising target for the management of sepsis and SIC patients. [ABSTRACT FROM AUTHOR]

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

Objective: Although guidelines support the efficacy of Modified Qing' E Formula (MQEF) in treating postmenopausal osteoporosis (PMOP), its underlying mechanisms remain incompletely understood. This retrospective investigation aims to elucidate MQEF's impact on serum exosomal miRNA expression in postmenopausal osteoporosis patients and to explore potential therapeutic mechanisms. Methods: Following ethical approval and registration, postmenopausal osteoporosis patients aged 50-85 years, meeting the diagnostic criteria were randomly selected and received MQEF decoction supplementary therapy. Serum samples were collected pre- and post-treatment, followed by isolation and sequencing of exosomal miRNAs. Differential miRNAs in serum exosomes were identified, and bioinformatics analysis was conducted to discern the principal exosomal miRNAs involved in MQEF's effects on PMOP and the associated signaling pathways. Results: Eighteen clinical blood samples were collected. A total of 282,185 target genes were detected across the three groups. 306 miRNAs exhibited altered expression in serum exosomes of PMOP patients, while MQEF intervention resulted in changes in 328 miRNAs. GO enrichment analysis revealed the immune and endocrine systems was pertained. KEGG enrichment analysis indicated associations between PMOP occurrence and MQEF treatment with cytokine interactions, oxidative phosphorylation, and the renin-angiotensin system. Intersectional analysis identified 17 miRNAs, including 2 consistent trends. miR-3188 as a potentially pivotal miRNA implicated in both PMOP occurrence and MQEF treatment. Conclusion: This study constitutes the first randomized, retrospective clinical exploration confirming that MQEF demonstrates regulatory influence over exosomal miRNA expression in PMOP patients' serum, its impact likely involves modulation of the immune and endocrine systems, as well as the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) of the kidney is responsible for renal regulation and homeostasis, and patients with chronic kidney disease frequently receive RAS blockades. The purpose of this study was to determine the connection between the stimulation of arsenic in rats and changes in transcription levels of RAS hormones, biochemical parameters and antioxidant enzymes. Twenty-five Wistar rats were divided into five groups (control, low, middle, high dose and high dose + α-tocopherol groups) and given oral doses of 8.2, 12.3 and 16.4 mg/kg sodium arsenite (NaAsO2) and 50 mg/kg α-tocopherol for two months. RT-PCR analysis in nephrocytes revealed that mRNA expression of p53, p21, p27, caspases (3, 7 and 9), ACE, AGT, AT1R, CYP1A1 and Bax was found to be upregulated by ~1.9, ~1.6, ~1.5, ~2.3, ~3.3, ~3, ~2, ~1.9, ~2.4, ~1.7 and ~3.3-fold, whereas that of cyclin A, cyclin B1, cyclin E1, CDK 1, CDK 2, Bcl-2, CAT, SOD, GPx, GR and GST was downregulated consistently in renal tissues of arsenic-exposed groups by ~0.6, ~0.5, ~0.4, ~0.5, ~0.6, ~0.5, ~0.6, ~0.4, ~0.6, ~0.5 and ~0.6-fold respectively. The activities of alkaline phosphatase, acid phosphatase and antioxidant enzymes were significantly reduced by 63%, 71%, 40%, 37% and 44% respectively, upon treatment with NaAsO2. Through this study, we can gain knowledge about the potential function of RAS enzymes and antioxidant enzymes against the detrimental effects of arsenic-induced oxidative stress due to altered transcription levels of RAS enzymes in Wistar rats. [ABSTRACT FROM AUTHOR]

Objectives Subjects and Methods Results Conclusions The renin‐angiotensin system (RAS) plays essential roles in cardiovascular and renal function regulation. Recent studies have shown that the RAS components are widely expressed in oral tissues, but their roles in oral diseases remain underexplored. This review aims to summarize the effects of the RAS in select oral diseases including oral squamous cells carcinoma (OSCC), periodontitis, oral submucous fibrosis (OSF), and ageusia/dysgeusia.Data searches were performed using PubMed, Web of Science and Scopus through July 2024. A narrative overview of current literature was undertaken to synthesize the contexts with elaboration and summary.In OSCC, ACE/Ang II/AT1R promotes OSCC by inducing angiogenesis, cell proliferation and invasiveness. Conversely, ACE/Ang II/AT2R and ACE2/Ang (1–7)/MasR inhibit OSCC progressions. In periodontitis, ACE/Ang II/AT1R upregulates inflammatory cytokines and promotes osteoclast differentiation factor RANKL, whereas ACE2/Ang (1–7)/MasR exerts opposite effects by preventing inflammation and alveolar bone loss. In OSF, Ang (1–7) counters the profibrotic and proinflammatory action of Ang II. In dysgeusia, Ang II suppresses salt taste responses and enhances sweet taste sensitivities, while Ang (1–7) exhibits opposite effects.The RAS cascade plays crucial roles in OSCC, periodontitis, OSF and ageusia/dysgeusia. The imbalanced RAS may aggravate the progression of these diseases. [ABSTRACT FROM AUTHOR]

This research letter published in the journal Circulation discusses the potential cardioprotective activity of a retro-enantiomer peptide called Angiotensin-(1-9) [Ang-(1-9) RE]. The authors synthesized this peptide and found that it interacts with the angiotensin receptor type 2 (AT2R) and displays increased stability in serum compared to the original peptide Ang-(1-9). The study conducted on spontaneously hypertensive rats (SHRs) showed that Ang-(1-9) RE reduced systolic blood pressure and was more effective than Ang-(1-9) in reducing cardiac hypertrophy and collagen content in the hearts of SHRs. The study suggests that Ang-(1-9) RE has promising therapeutic applications for cardiovascular diseases. The text also briefly mentions the Iran Pasteur Institute, which has played a significant role in controlling infectious diseases in Iran and is considered a major component of Iran's healthcare and research infrastructure. [Extracted from the article]

Pulmonary arterial hypertension (PAH) is characterized by an increase of a pressure in the pulmonary circulation; PAH is accompanied by activation of the sympathetic (SNS) and the renin-angiotensin-aldosterone system (RAAS). However, PAH-associated changes in baroreceptor regulation of systemic circulation, which is tightly interwoven with SNS and RAAS, have not been studied. The baroreceptor response (BRR) was studied in a chronic monocrotaline (MCT) model of PAH in rats (Wistar, 290 ± 30 g, 2–4 months). Phenylephrine as an agonist of α1-adrenergic receptor and sodium nitroprusside as NO donor were gradually administered to chronically catheterized, non-anesthetized control animals and animals with PAH (4 weeks after MCT administration) to induce vasomotor responses. Mean arterial pressure and heart rate (HR) were recorded under the action of vasoactive compounds alone or under the action of vasoactive compounds in presence of angiotensin-II (ATII), atropine. The parameters characterizing baroreceptor change in HR including maximal and minimal heart rate (HRmax, HRmin), reflex tachycardia (TBRR) and bradycardia (BBRR), range (ABRR) and the baroreceptor response sensitivity index (SIBRR) were calculated. A significant decrease in HRmax, TBRR, ABBR (but not BBRR), as well as the sensitivity index of BRR was observed in rats with PAH. ATII induces significant and different changes in the BRR parameters in control rats and in rats with PAH if administered 4 weeks after the start of the experiment. In rats with PAH, ATII causes less pronounced changes in HRmax, TBRR, and BBRR than in control animals. ATII insignificantly affects parasympathetic component of the baroreceptor reflex in rats with PAH. Thus, at least in the MCT-mediated model in rats, PAH significantly deteriorates the baroreceptor regulation of HR. This effect manifests in a decrease in the range and sensitivity of the baroreceptor response. Also, PAH unequally affects the sympathetic and parasympathetic control of the baroreceptor regulation of HR. On the other hand, ATII exhibits weak ability to alter BRR in rats with HAP. In conclusion, PAH leads to a disfunction of immediate, reflex mechanisms HR and systemic circulation control. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1–7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes. NEW & NOTEWORTHY: The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function. [ABSTRACT FROM AUTHOR]

There are diverse pathophysiological mechanisms involved in acute kidney injury (AKI). Among them, overactivity of the renin-angiotensin system (RAS) has been described. Angiotensin-converting enzyme 2 (ACE2) is a tissue RAS enzyme expressed in the apical border of proximal tubules. Given the important role of ACE2 in the metabolism of angiotensin II, this study aimed to characterize kidney and urinary ACE2 in a mouse model of AKI. Ischemia-reperfusion injury (IRI) was induced in C57BL/6 mice by clamping of the left renal artery followed by removal of the right kidney. In kidneys harvested 48 h after IRI, immunostaining revealed a striking maldistribution of ACE2 including spillage into the tubular lumen and the presence of ACE2-positive luminal casts in the medulla. In cortical membranes, ACE2 protein and enzymatic activity were both markedly reduced (37 ± 4 vs. 100 ± 6 ACE2/β-actin, P = 0.0004, and 96 ± 14 vs. 152 ± 6 RFU/μg protein/h, P = 0.006). In urine, full-length membrane-bound ACE2 protein (100 kDa) was markedly increased (1,120 ± 405 vs. 100 ± 46 ACE2/µg creatinine, P = 0.04), and casts stained for ACE2 were recovered in the urine sediment. In conclusion, in AKI caused by IRI, there is a marked loss of ACE2 from the apical tubular border with deposition of ACE2-positive material in the medulla and increased urinary excretion of full-length membrane-bound ACE2 protein. The deficiency of tubular ACE2 in AKI suggests that provision of this enzyme could have therapeutic applications and that its excretion in the urine may also serve as a diagnostic marker of severe proximal tubular injury. NEW & NOTEWORTHY: This study provides novel insights into the distribution of kidney ACE2 in a model of AKI by IRI showing a striking detachment of apical ACE2 from proximal tubules and its loss in urine and urine sediment. The observed deficiency of kidney ACE2 protein and enzymatic activity in severe AKI suggests that administration of forms of this enzyme may mitigate AKI and that urinary ACE2 may serve as a potential biomarker for tubular injury. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzymes (ACE) are well-known for their roles in both blood pressure regulation via the renin-angiotensin system as well as functions in fertility, immunity, hematopoiesis, and many others. The two main isoforms of ACE include ACE and ACE-2 (ACE2). Both isoforms have similar structures and mediate numerous effects on the cardiovascular system. Most remarkably, ACE2 serves as an entry receptor for SARS-CoV-2. Understanding the interaction between the virus and ACE2 is vital to combating the disease and preventing a similar pandemic in the future. Noninvasive imaging techniques such as positron emission tomography and single photon emission computed tomography could noninvasively and quantitatively assess in vivo ACE2 expression levels. ACE2-targeted imaging can be used as a valuable tool to better understand the mechanism of the infection process and the potential roles of ACE2 in homeostasis and related diseases. Together, this information can aid in the identification of potential therapeutic drugs for infectious diseases, cancer, and many ACE2-related diseases. The present review summarized the state-of-the-art radiotracers for ACE2 imaging, including their chemical design, pharmacological properties, radiochemistry, as well as preclinical and human molecular imaging findings. We also discussed the advantages and limitations of the currently developed ACE2-specific radiotracers. [ABSTRACT FROM AUTHOR]

Background: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. Methods: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. Results: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5–8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. Conclusions: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis. [ABSTRACT FROM AUTHOR]

Gynecological cancers constitute a significant health burden for females worldwide, with cervical, endometrial and ovarian cancer being the most common types. The renin-angiotensin-aldosterone (RAA) system regulates blood pressure and is involved in various diseases, such as hypertension and heart failure. However, several studies have found that the angiotensin-1 receptor (AT1R) pathway is activated in various types of cancers, including breast, pancreatic and colorectal cancers. The AT1R receptor, in particular, has been shown to induce proliferation, neovascularization and fibrosis; therefore, its activation may induce cancer progression. Several epidemiological studies have found an association between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) with reduced cancer incidence; however, others have reported unclear or even deleterious associations between ARB use and cancers. These conflicting results necessitate the further exploration of the influence of the RAA system in the development of gynecological cancers. Several new factors in the RAA system have been identified, including angiotensin-(1-7) and angiotensin-(1-9), which have been shown to play a crucial role in preventing cell proliferation and, possibly, cancer progression. The present review discusses the association between the RAA system and gynecological cancers, specifically endometrial, ovarian and cervical cancers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension). [ABSTRACT FROM AUTHOR]

Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin–angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang‐(1–7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang‐(1–7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang‐(1–7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang‐(1–7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Abstract Background The exact pathogenesis of Huntington’s disease (HD) remains unclear. However, mitochondrial dysfunction and oxidative stress are supposed to play a significant role. The objective of this study was to examine the possible neuroprotective effect of Lisinopril (Lisino) in a 3-nitropropionic acid-produced HD in rats. Methods Sixty-four rats were divided into four groups (16/group): Group (1): Normal control group, Group (2): Lisinopril control group, Group (3): 3-NP non-treated group, and Group (4): (3-NP + Lisinopril) group. Behavior assessments (open field test, rotarod test, grip strength test) were performed along with different histological and biochemical parameters. Results Lisinopril upregulated the expression of the ACE2/Ang1-7/MAS receptor (MasR) axis of RAS, which triggered the PI3K/Akt pathway and prompted the CREB/BDNF neurogenesis signal. Furthermore, Lisinopril remarkably downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6), decreased apoptotic markers (p53, BAX/Bcl2 ratio, Cyt-c and caspase-3) and upgraded the mitochondrial TFAM content and SDH activity along with restoration of the redox mechanism by recovering SOD, catalase, GSH and Nrf2. Conclusion Notably, the outcomes of this study disclosed that Lisinopril could be a future neuroprotective therapeutic candidate against HD.