Search Results (428)

Chronic kidney disease (CKD) is a global health challenge, marked by significant morbidity and mortality and a rising economic burden. Despite established therapies such as renin–angiotensin system (RAS) inhibitors and SGLT2 inhibitors, a substantial residual risk of CKD progression and cardiovascular events persists. This gap is largely attributed to the sustained overactivation of the mineralocorticoid receptors by aldosterone, a key driver of renal inflammation and fibrosis. This review aims to bridge the understanding between aldosterone’s intricate pathophysiology and emerging therapeutic strategies designed to address this unmet clinical need. We discuss the physiological regulation of aldosterone synthesis and secretion, the phenomenon of aldosterone breakthrough under conventional RAS blockade and the diverse mechanisms through which aldosterone mediates kidney damage. We evaluate novel non-steroidal mineralocorticoid receptor antagonists, exemplified by finerenone, which demonstrate superior safety profiles and valid efficacy in reducing renal and cardiovascular outcomes in clinical trials. Additionally, we examine aldosterone synthase inhibitors as an upstream therapeutic approach to directly reduce aldosterone production. These novel agents represent promising avenues to mitigate residual risk and improve long-term outcomes for patients with CKD. Full article

Background/Objective: Sacubitril/Valsartan are a combination drug approved for heart failure treatment, known to enhance natriuretic peptide activity and inhibit the renin–angiotensin–aldosterone system (RAAS). While its clinical efficacy is well-established, its broader impact on human metabolism remains insufficiently characterized. This study aimed to explore the time-resolved metabolic changes induced by Sacubitril/Valsartan in healthy individuals using an untargeted metabolomics approach. Methods: Fourteen healthy male volunteers received a single oral dose of Sacubitril/Valsartan (200 mg; 97.2 mg Sacubitril and 102.8 mg Valsartan) across two phases separated by a two-week washout period. Plasma samples were collected at eight individualized time points based on pharmacokinetic profiles. Metabolites were extracted and analyzed using high-resolution liquid chromatography–mass spectrometry (LC-QToF HRMS). Data processing included peak alignment, annotation via HMDB and METLIN, and statistical modeling through multivariate (PLS-DA, OPLS-DA) and univariate (ANOVA with FDR correction) analyses. Results: Out of 20,472 detected features, 13,840 were retained after quality filtering. A total of 315 metabolites were significantly dysregulated (FDR p < 0.05), of which 31 were confidently annotated as endogenous human metabolites. Among these, key changes were observed in the pyrimidine metabolism pathway, particularly elevated levels of uridine triphosphate (UTP) associated with cellular proliferation and metabolic remodeling. OPLS-DA models demonstrated clear separation between pre-dose and Cmax samples (R²Y = 0.993, Q² = 0.768), supporting the robustness of the time-dependent effects. Conclusions: This is the first study to characterize the dynamic metabolomic signature of Sacubitril/Valsartan in healthy humans. The findings reveal a distinctive perturbation in pyrimidine metabolism, suggesting possible links to drug mechanisms relevant to cardiac cell cycle regulation. These results underscore the utility of untargeted pharmacometabolomics in uncovering systemic drug effects and highlight potential biomarkers for monitoring therapeutic response or guiding precision treatment strategies in heart failure. Full article

Diabetes mellitus (DM) poses an increasingly high global health burden nowadays, while in adults, chronic kidney disease (CKD) associated with DM impacts 20–40% of those with the condition. Effective management of CKD in patients with diabetes necessitates a comprehensive, multidisciplinary approach. Numerous factors, including glomerular hyperfiltration, oxidative stress, inflammation, and hypoxia are linked to the advancement of diabetic kidney disease (DKD). Currently, no specific treatment for DKD has been established, prompting extensive exploration of new approaches. Renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter 2 inhibitors have demonstrated renoprotective effects in various human clinical trials. Additionally, glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists have been reported as effective in managing DKD, while new therapeutic candidates are also under investigation, such as soluble guanylate cyclase activators and aldosterone synthase inhibitors. Recent evidence has shown that treating diabetic nephropathy by reducing albuminuria levels and retarding its progression is a complex skill. The purpose of this review is to support the impressive results that appear in reducing albuminuria and the progression of diabetic nephropathy with early and intensive combination treatment compared to the recently emerged conventional monotherapy, with agents that act on different pathophysiological mechanisms. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS’s influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This review provides a comprehensive overview of classical and alternative RAAS pathways, focusing on the dual roles of angiotensin II (Ang II) and angiotensin-(1–7) (Ang 1–7), mediated through AT1R, AT2R, MasR, and MrgD receptors. We discuss molecular signaling cascades, including mitochondrial, nuclear, and caveolae-mediated mechanisms, and explore the impact of RAAS modulation on hepatic fibrosis, vascular remodeling, and autoimmune inflammation. Genetic models and emerging pharmacologic strategies illustrate tissue-specific RAAS actions, emphasizing the therapeutic potential of enhancing the ACE2/Ang 1–7/Mas axis while inhibiting the deleterious ACE/Ang II/AT1R signaling. Furthermore, we highlight implications for veterinary medicine, particularly in canine chronic inflammatory enteropathies, where RAAS dysfunction may contribute to treatment resistance. Understanding RAAS complexity and inter-receptor crosstalk is essential for developing new therapeutic strategies targeting cardiovascular, hepatic, and inflammatory diseases in both human and veterinary contexts. Full article

COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin–angiotensin–aldosterone system (RAAS), the kininogen–kinin–kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects. Full article

Asthma is a multifactorial respiratory disease that naturally occurs in horses, humans, and cats, presenting common clinical signs and species-specific mechanisms. This review addresses the impact of asthma on the cardiovascular and neurological systems, with a primary focus on horses. It highlights the need for new biomarkers beyond the respiratory system due to diagnostic difficulties in animals. A comprehensive literature search was conducted using PubMed and Google Scholar, focusing on cardiovascular and neurological manifestations of asthma in humans, horses, cats, and experimental animal models. Studies were qualitatively compared, noting species-specific differences and mechanisms. Humans with asthma show an increased risk of cardiovascular disease and elevated cardiac biomarkers during exacerbations, while horses develop pulmonary hypertension and vascular remodeling. Cats exhibit significant pulmonary vascular changes. Heart rate variability analysis reveals altered autonomic function in humans and horses. Increased peripheral airway innervation and cough reflex sensitivity are noted across species. The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in asthma pathophysiology in murine models. Asthma impacts the cardiovascular and nervous systems differently across species, emphasizing the importance of comparative medicine. Future research should integrate cardiovascular, autonomic, and inflammatory pathways to develop effective therapeutic approaches in human and veterinary medicine, leveraging insights from naturally occurring asthma models. Full article

Recent studies have demonstrated that the development and progression of hypertensive kidney injury comprise not only elevated systemic blood pressure but also a complex interplay of cellular, molecular, and genetic mechanisms. In this report, we outline the key emerging pathways—ranging from dysregulated renin–angiotensin system signaling, oxidative stress, immune-mediated inflammation, and metabolic abnormalities to epigenetic alterations and genetic susceptibilities—that contribute to kidney damage in hypertensive conditions. In addition, we also discuss precision medicine approaches like biomarker-directed therapies, pharmacologically targeted therapies, and device-based innovations for modulating these pathways. This integrative review emphasizes the application of omics technologies and genetically guided interventions to better stratify patients and offer personalized care for hypertensive kidney disease. Full article

The pivotal role of angiotensin II (AngII) in cardiovascular disease has been firmly established, as evidenced by a robust body of literature and the broad clinical application of AngII-inhibiting therapies. AngII type 1 receptor is the primary mediator of AngII action, and its activation initiates a multitude of cellular responses that contribute to the development of hypertension, structural changes in the heart and vasculature, and damage to target organs. This review examines AngII from a different perspective, exploring the link between the renin–angiotensin–aldosterone system and cardiovascular risk beyond hypertension, with particular emphasis on atherosclerosis development and progression. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Hypertension is an important risk factor for cardiovascular diseases. High salt intake when consumed with excess fructose enhances hypertension and resultant cardiovascular disease. Usually, the small intestine absorbs dietary fructose, and the proximal tubule of kidney reabsorbs filtered fructose into the circulation with the help of different transporters including SGLT4 and SGLT5. Very recently, SGLT5 mRNA has also been found to be expressed in the heart. High-fructose diet stimulates the sympathetic nervous system and renin–angiotensin–aldosterone (RAAS) activity, of which both are responsible for endothelial dysfunction and are associated with salt-sensitive hypertension. Few studies exist regarding the effects of SGLT4 and SGLT5 on cardiovascular function and blood pressure. However, SGLT4 gene knockout does not alter fructose-associated impact on blood pressure. In contrast, blood pressure does not increase in SGLT5 knockout rats even during fructose consumption. Given that limiting fructose and salt consumption as a public health strategy has proven challenging, we hope that studies into SGLT4 and SGLT5 transporters will open new research initiatives to address salt-sensitive hypertension and cardiovascular disease. This review highlights current information about SGLT4 and SGLT5 on fructose absorption, salt-sensitive hypertension, cardiovascular disease and points the way for the development of therapeutic fructose inhibitors that limit adverse effects. Full article

Background/Objectives: Perioperative hypotension during kidney transplantation poses a risk to graft function and survival. Angiotensin II (AngII) is an endogenous vasoconstrictor targeting the renin–angiotensin–aldosterone system (RAAS) to increase blood pressure. Black patients may have a different response to synthetic angiotensin II (AT2S) compared to non-Black patients, given differential expressions in renin profiles. The purpose of this study is to assess the difference between Black and non-Black patients in total vasopressor duration and usage when AT2S is first line for hypotension during kidney transplantation. Methods: A single-center, retrospective cohort study comparing Black and non-Black patients who required AT2S as a first-line vasopressor for hypotension during the perioperative period of kidney transplantation. Results: The primary outcome evaluating total usage of vasopressors found that Black patients required longer durations of vasopressors (36.9 ± 66.8 h vs. 23.7 ± 31.7 h; p = 0.022) but no difference in vasopressor amount (0.07 ± 0.1 NEE vs. 0.05 ± 0.1 NEE; p = 0.128) compared to non-Black patients. Regression analysis found that body weight was associated with the duration of vasopressors (p < 0.05), while baseline systolic blood pressure was inversely associated with it. Longer duration of vasopressors and duration of transplant surgery were associated with delayed graft function in regression analysis (p < 0.05). Conclusions: Black patients had a longer duration of vasopressors, but this was not driven by differences in usage of AT2S. As baseline weight was significantly higher in Black patients and associated with duration of usage, perhaps the metabolic differences in our Black patients led to the observed differences. Regardless, longer durations of vasopressors were associated with delayed graft function, making this an area of utmost importance for continued investigation. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Background: SARS-CoV-2 infection has been associated with long-term health consequences, including dysregulation of the renin–angiotensin–aldosterone system (RAAS). This study aimed to evaluate long-term changes in selected RAAS-related biochemical parameters in repeat convalescent plasma donors, focusing on enzymes and peptides involved in vascular regulation and inflammation. Methods: Thirty repeat convalescent plasma donors were enrolled, each providing four serum samples at defined time points post-infection. Samples were collected during Period 1 (≤60 days), Period 2 (61–90 days), Period 3 (91–120 days), and Period 4 (>120 days) after confirmed SARS-CoV-2 infection. The analyzed parameters included angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1–7 (Ang 1–7), angiotensin 1–9 (Ang 1–9), ACE, ACE2, ADAM10, and ADAM17. Concentrations were determined using ELISA assays. The control group consisted of pre-pandemic serum samples from healthy individuals. Results: An initial post-infection increase was observed in most parameters, particularly in Period 1. Over time, levels of several markers declined, yet Ang 1–7 and Ang 1–9 remained elevated compared to controls even beyond 120 days. Significant correlations (p < 0.05) were found between ADAM10, ADAM17, and angiotensin peptides, suggesting prolonged RAAS modulation. Metalloproteinases were notably elevated early after infection, potentially contributing to inflammatory and cardiovascular responses. Conclusions: The findings indicate a transient but measurable biochemical response of the RAAS following SARS-CoV-2 infection, with most parameters normalizing after 120 days. However, the sustained elevation of certain markers suggests a potential long-term impact on vascular homeostasis, warranting further investigation. Full article

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or type 2 (AT2R) receptors. AT1R activation promotes vasoconstriction, oxidative stress, endothelial dysfunction, peripheral vascular resistance, and atherosclerosis, all of which substantially contribute to cellular senescence and organismal ageing. Conversely, AT2R activation counteracts these effects by inducing vascular relaxation and attenuating vascular cell proliferation and migration, offering protection against occlusive vascular disease. Additionally, conversion of angiotensin II to angiotensin (1-7) or angiotensin I to angiotensin (1-9) by ACE2 provides further cardiovascular protection by lowering oxidative stress, inflammation, and abnormal cell growth. Bearing these in mind, measures to control angiotensin II synthesis or receptor activity have been at the forefront of antihypertensive treatment. This paper briefly reviews the RAAS and explores the dual role of angiotensin II in promoting disease and mediating vascular protection, with a focus on its impact on ageing and cardiovascular pathology. Full article

Contrast-associated acute kidney injury (CA-AKI) is a known complication of endovascular procedures using an iodinated contrast medium (ICM), especially in patients with peripheral artery disease (PAD) and chronic kidney disease (CKD). This retrospective study evaluated the incidence and risk factors of AKI in patients with PAD and CKD undergoing diagnostic angiography or endovascular intervention using carbon dioxide (CO₂) as the primary contrast medium, with optional bailout ICM use. We included 340 patients who underwent peripheral angiography or intervention between September 2014 and December 2020. CO₂ was used as the primary contrast medium for all patients, as the majority were classified with advanced CKD stages 3–5 according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Bailout ICM was used in 80% of cases (mean 21.23 ± 14.09 mL). Postinterventional AKI occurred in 13.2% of patients, with over 70% classified as stage 1. Seven patients required new dialysis within 7 days. Multivariate analysis identified hypertension, heart failure, and coronary artery disease as independent AKI risk factors. Statin or Renin–Angiotensin–Aldosteron System (RAAS) inhibitor use and higher pre-interventional GFR were protective. AKI remains common in patients undergoing CO₂-guided peripheral procedures. Further studies are needed to explore underlying mechanisms and outcomes. Full article