Search Results (263)

Pulmonary hypertension complicating chronic obstructive pulmonary disease (COPD-PH) has a worse prognosis than airflow limitation alone but its pathogenesis is thought to be primarily due to alveolar hypoxia affecting pulmonary circulation. Two observations are not fully explained by this model. First, the majority of exacerbations of COPD are infectious and there is a stable frequent-exacerbator phenotype that is not fully accounted for by spirometric severity. Second, the airways of COPD are not sterile. They are home to a resident microbial community that changes as the disease progresses and the gut microbial community also undergoes disease-associated changes. This review examines whether microbial factors actively contribute to pulmonary vascular remodelling or merely reflect advanced disease. Three candidate exposures are considered: chronic airway colonisation, dysbiosis of the airway and gut communities and recurrent infectious exacerbation. We then examine the virulence mechanisms and host-recognition pathways of non-typeable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa, rhinovirus, influenza viruses, respiratory syncytial virus and SARS-CoV-2. We then trace the pathways linking microbial recognition to vascular injury: Toll-like receptor signalling and NF-κB activation; interleukin-6, tumour necrosis factor-α and interleukin-1β; endothelin-1 upregulation against nitric oxide depletion; reactive oxygen species and hypoxia-inducible factor signalling converging with hypoxic pulmonary vasoconstriction; and, along the gut–lung axis, lipopolysaccharide translocation, trimethylamine N-oxide and depletion of short-chain fatty acid-producing taxa. Therapeutically, there is evidence and a vascular rationale for interventions that decrease exacerbation frequency. Pulmonary vasodilators have a sound physiological rationale, although their clinical efficacy is frequently limited by worsening ventilation–perfusion mismatch. Current evidence supports biological plausibility rather than demonstrated causality: no direct longitudinal human study has established that microbial alterations or microbial exposure cause pulmonary vascular remodelling in COPD-PH. We identify study designs capable of directly testing this hypothesis. Full article

Antibody-mediated rejection (AMR) remains a major cause of kidney allograft injury and loss. Although donor-specific antibodies against human leukocyte antigens (HLA-DSAs) are central to humoral alloimmunity, they do not explain all cases of microvascular inflammation or graft dysfunction. This review critically evaluates non-HLA antibodies as potential mediators of allograft injury and markers of dysregulated humoral immunity by integrating functional, experimental, clinicopathological, and clinical evidence. Receptor-targeting antibodies, especially those against the angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), have the strongest evidence for direct pathogenicity. Antibodies against major histocompatibility complex class I-related chain A (MICA) and glutathione S-transferase theta-1 (GSTT1) reflect non-HLA alloimmunity, whereas antibodies targeting perlecan-derived LG3, vimentin, and injury-associated antigens may arise through secondary autoimmunity and mark broader humoral activation. We propose that selected pathogenic non-HLA antibodies participate in a feed-forward cycle of graft injury, antigen exposure, epitope spreading, and humoral amplification, although this model requires longitudinal validation. Crucially, non-HLA antibody positivity alone should neither establish AMR nor guide antibody-specific treatment. Its interpretation should be target-specific and integrated with HLA-DSAs, histopathology, molecular findings, graft function, and evidence of immune activation. Full article

Background: Chronic coronary syndrome (CCS) has evolved from a stenosis-centered concept to a dynamic clinical entity in which obstructive and non-obstructive coronary disease, microvascular dysfunction, and vasomotor abnormalities coexist with complex neurohormonal and endocrine activation. However, CCS has rarely been examined through an integrated endocrine lens, and no unified hormonal-phenotype framework currently links neurohormonal, sex-hormone, thyroid, and cardiometabolic pathways across CCS presentations. Objective: To synthesize contemporary evidence on how neurohormonal and endocrine pathways shape CCS phenotypes and to outline potential endocrine targets for phenotype-guided therapy. Methods for Synthesis of Data: We performed a structured literature appraisal in PubMed, Embase, the Cochrane Library, and ScienceDirect from inception to May 2026, using CCS/stable coronary artery disease and hormone-related search terms, and included comparative clinical studies in adults that evaluated neurohormonal or endocrine interventions with clinically relevant cardiovascular outcomes. Results: From 851 records, 34 studies were retained for qualitative synthesis, encompassing randomized trials, observational cohort studies, systematic reviews, and consensus documents. These data support a central role for renin–angiotensin–aldosterone and sympathetic activation, counterregulatory natriuretic peptides, endothelin-1, sex and thyroid hormones, and adipose-derived mediators in modulating CCS phenotypes, symptoms, and residual risk. Hormone-targeting therapies—including RAAS blockade, beta-blockers, mineralocorticoid receptor antagonists, sex- and thyroid-hormone modulation, and cardiometabolic agents such as GLP-1 receptor agonists and SGLT2 inhibitors—show variable yet often significant impact on outcomes across specific CCS subsets. Conclusions: CCS is best conceptualized as a state of coordinated neurohormonal and endocrine disturbance rather than a purely anatomical disease. A hormonal phenotype framework may support more biologically rational, individualized management and define a research agenda for phenotype-stratified trials in CCS. This review proposes a hormonal-phenotype framework that is conceptually novel compared with anatomy- or comorbidity-based CCS classifications and is intended to be hypothesis-generating rather than prescriptive, by highlighting specific knowledge gaps and potential endocrine targets for future phenotype-guided trials. Full article

The aim of this study was to summarize current evidence on dust-related diseases of the bronchopulmonary system, medicinal plants, herbal formulations, and their underlying mechanisms of action. A literature review was conducted based on publications indexed in ScienceDirect, Google Scholar, SciFinder, Scopus, and Medline (PubMed), focusing on the mechanisms underlying dust-related diseases of the bronchopulmonary system, pneumoconiosis, and the potential of phytotherapeutic approaches to modulate these processes. The following keywords were used: bronchopulmonary system, pneumoconiosis, dust-related lung diseases, medicinal plants, herbal preparations, pulmonary rehabilitation, and lymphatic sanitation. The pathogenesis of pneumoconiosis involves the deposition of inhaled dust particles in the lung tissue, followed by chronic inflammation, oxidative stress, and progressive fibrosis. In experimental models, flavonoids, alkaloids, terpenoids, glycosides, tannins, and other phytochemical groups have demonstrated therapeutic potential in bronchopulmonary diseases. Among the compounds investigated, emodin, celastrol, kaempferol, sodium tanshinone IIA sulfonate, astragaloside IV, and dioscin have shown promising effects by modulating key signaling pathways and reducing inflammatory responses. Experimental evidence indicates that these phytochemicals can target major pathways involved in inflammation and fibrogenesis, thereby exerting antioxidant, anti-inflammatory, and antifibrotic effects. The lymphatic system also contributes to the pathogenesis of pneumoconiosis by transporting inhaled dust particles to regional lymph nodes, where their accumulation may promote lymph node sclerosis. Therefore, lymphatic sanitation may represent an important therapeutic mechanism of action of herbal formulations in pneumoconiosis. Our proposed lymphotropic herbal formulation enhances physiological lymphatic drainage and may positively influence the motility and functional activity of the tracheobronchial lymph nodes. The therapeutic potential of medicinal plants and herbal formulations in pneumoconiosis is supported by experimental findings for Tripterygium wilfordii (celastrol, through suppression of the EDNRB/Kng1–(endothelin receptor type B/kininogen1), Delphinium, Camellia, and Berberis species (kaempferol, through inhibition of TLR4 (Toll-like receptor 4 signaling), Astragalus membranaceus (astragaloside IV, through antifibrotic activity mediated by inhibition of the TGF-β1 (transforming growth factor beta 1)/Smad3 (SMAD family member 3) pathway), and Reynoutria japonica Houtt., Rheum, and Aloe species (emodin, through inhibition of Smad3 and NF-κB (nuclear factor kappa B) phosphorylation and reduction of TGF-β1, α-SMA (alpha-smooth muscle actin), collagen I, TNF-α (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta) levels in lung tissue). For these and several other medicinal plants and their flavonoids, antifibrotic activity has been demonstrated through inhibition of the Akt/NF-κB (protein kinase B/nuclear factor kappa B) signaling pathway. A promising direction for future research is to evaluate the combined use of herbal formulations with established antifibrotic agents to determine whether synergistic therapeutic effects can be achieved. Full article

G protein-coupled receptors (GPCRs) are dynamic allosteric proteins whose signaling properties are governed by reciprocal communication between extracellular ligand-binding sites and intracellular transducer interfaces. Although classical pharmacological models established the concept that ligand binding and G protein coupling are thermodynamically linked, recent structural, biophysical, and computational studies have revealed a far more complex picture in which GPCRs exist as ensembles of interconverting conformational states. Accumulating evidence indicates that G proteins function not only as downstream signaling effectors but also as endogenous allosteric modulators. By reshaping receptor conformational landscapes, G protein coupling can influence the structure and dynamics of orthosteric ligand-binding pockets, thereby regulating ligand affinity, binding kinetics, and receptor selectivity. These findings support a bidirectional model of GPCR signaling in which information is transmitted not only from ligand-binding sites to intracellular signaling partners but also in the reverse direction through receptor-wide allosteric networks. Disease-associated mutations of endothelin A receptor (ETAR) provide in vivo evidence that structural perturbations located far from orthosteric ligand-binding sites can alter ligand recognition through long-range allosteric communication. In addition, emerging studies of positive allosteric modulators demonstrate the therapeutic potential of selectively stabilizing ligand–receptor–G protein complexes. These observations suggest that ligand recognition, receptor activation, and transducer coupling should be viewed as integrated properties of a dynamic receptor–ligand–transducer ensemble. This perspective provides a conceptual framework that links classical GPCR pharmacology, structural biology, disease mechanisms, and next-generation drug discovery. Full article

Background/Objectives: Brain pericytes are contractile mural cells of the neurovascular unit whose responses to endothelin-1 (ET-1) are mediated primarily by endothelin type A (ETA) receptors. ET-1/ETA signaling has been implicated in pathological pericyte contraction in neurovascular disorders such as Alzheimer’s disease and in cerebrovascular dysfunction after subarachnoid hemorrhage, motivating pharmacological evaluation of selective ETA receptor antagonists at the pericyte level. Clazosentan is a selective ETA receptor antagonist used clinically for cerebral vasospasm; however, its pharmacodynamic effects on brain pericytes remain insufficiently characterized. Methods: Pericyte impedance-based contractile and recovery responses to ET-1 were evaluated by xCELLigence real-time cell index analysis. Pericyte viability, morphology, and ETA protein abundance were examined using Cell Counting Kit-8 assay, immunocytochemistry, and Western blotting. As a secondary barrier-related assessment, transendothelial electrical resistance (TEER) was measured in primary rat brain endothelial cell-based in vitro blood–brain barrier models. Results: ET-1 induced impedance-based contractile responses with a concentration-related trend, followed by recovery responses, and increased ETA protein abundance in a time- and concentration-related manner; clazosentan significantly attenuated ET-1-induced ETA upregulation. Repeated ET-1 exposure was associated with an enhanced subsequent ET-1-induced impedance-based contractile response and a more sustained response, suggesting contractile sensitization; both effects were significantly attenuated by clazosentan. Clazosentan did not overtly disrupt TEER-assessed barrier properties. Conclusions: These findings suggest that ET-1/ETA signaling may shift brain pericytes toward a sensitized contractile response state and that selective ETA blockade by clazosentan attenuates this process without overtly disrupting TEER-assessed barrier properties under the present in vitro conditions. These observations support further pharmacological characterization of clazosentan as a modulator of pericyte ET-1 responses. Full article

Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway. Full article

Background: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), termed COPD-associated pulmonary hypertension (COPD-PH), and is associated with worse clinical outcomes. The efficacy and safety of pulmonary vasodilators in COPD-PH remain uncertain. Methods: We performed a systematic review and meta-analysis of randomized studies evaluating pulmonary vasodilators in adults with COPD-PH. Fifteen studies were identified, with 11 contributing to quantitative analyses. Outcomes included six-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), partial pressure of arterial oxygen (PaO₂), and systolic pulmonary arterial pressure (sPAP). Results: Pulmonary vasodilators significantly reduced mPAP (MD −3.88 mmHg, 95% CI −7.23 to −0.53) and PVR (SMD −0.90, 95% CI −1.70 to −0.10). However, no significant improvements were observed in 6MWD or PaO₂. An exploratory composite hemodynamic score supported an overall hemodynamic benefit. Subgroup analyses suggested a more favorable profile for nitric oxide donors, whereas endothelin receptor antagonists were associated with worsened oxygenation. Conclusions: Pulmonary vasodilators improve pulmonary hemodynamics in COPD-PH but do not consistently improve exercise capacity or oxygenation. Current evidence does not support routine use outside specialized centers or clinical trials, and treatment effects appear to vary by drug class. Full article

Glomerulosclerosis is not an independent disease entity but rather a common histopathological endpoint shared by diverse glomerular diseases and chronic kidney disorders. It represents the final common pathway of progressive glomerular injury and is a major determinant of chronic kidney disease (CKD) progression. Accordingly, this review focuses on the shared cellular and molecular mechanisms that drive glomerulosclerosis, together with current diagnostic strategies, mechanism-based therapeutic approaches, and future directions toward precision nephrology. We begin by summarizing the structural and functional features of the glomerulus and outlining the key molecular mechanisms that drive sclerosis, including podocyte loss, mesangial matrix expansion, endothelial dysfunction, inflammation, and fibrosis-related signaling pathways. The clinical and pathological classifications of glomerular diseases associated with glomerulosclerosis—ranging from primary and secondary focal segmental glomerulosclerosis (FSGS) to diabetic, hypertensive, and immune-mediated forms—are discussed in detail. We further review current diagnostic approaches, including renal biopsy patterns, emerging biomarkers, and novel imaging and digital pathology tools that enable earlier and more precise assessment of disease severity. Recent advances in treatment are summarized across conservative, immunologic, and targeted therapeutic categories, with emphasis on SGLT2 inhibitors, endothelin receptor antagonists, immunomodulatory agents, and antifibrotic compounds. Finally, we highlight rapidly evolving therapeutic and technological advances, including podocyte-directed interventions, APOL1-targeted therapies, RNA- and gene-based therapeutics, and artificial intelligence-driven precision nephrology. These emerging approaches are reshaping the management paradigm of glomerular diseases by enabling molecular disease stratification and personalized treatment strategies. Despite substantial progress, significant unmet needs remain, particularly concerning early detection, individualized treatment selection, and the marked heterogeneity of disease mechanisms across patient populations. Overall, this review provides an integrated framework for understanding glomerulosclerosis as a shared pathological endpoint of diverse glomerular diseases and highlights emerging mechanism-based therapeutic strategies that support the transition toward precision nephrology. Full article

This review examines how structural injury to the endothelial glycocalyx is known to initiate the collapse of caveolin-1-dependent caveolae, and how this may influence the dysregulation of endothelin type B receptors. The glycocalyx, caveolae, and endothelin type B receptors are proposed to form an integrated mechanosensory axis that coordinates shear-dependent signaling, redox control, and endothelin peptide clearance. Under physiological flow conditions, heparan sulfate-mediated mechanotransduction is known to sustain caveolin-1 expression, which preserves caveolar organization, endothelial nitric oxide synthase coupling, and localization of endothelin type B receptors. Under disturbed flow or inflammatory stress, enzymatic shedding of the glycocalyx is associated with reduced caveolin-1 stability and subsequent disruption of caveolar microdomains. These structural alterations coincide with the uncoupling of endothelial nitric oxide synthase, increased reactive oxygen species generation, enhanced endothelin-1 transcription, and possibly the impaired localization of the endothelin type B receptors meant to clear endothelin-1 peptides. The combination of these processes suggests a potentially self-amplifying interaction between mechanotransductive failure, increased oxidative stress, and endothelin imbalance. The objective here is to reframe the current understanding of glycocalyx degradation and caveolar collapse as direct upstream contributors to endothelin type B receptor dysfunction, while simultaneously highlighting the preservation of this pathway as a potential therapeutic focus in vascular diseases such as hypertension and atherosclerosis. A stronger mechanistic definition of the relationship between glycocalyx degradation, caveolae destabilization, and altered endothelin type B receptor function is necessary to clarify how vascular injury may lead to persistent endothelial dysfunction. Future research in this area may present opportunities for therapeutic interventions focused on preservation or restoration of glycocalyx integrity and function and may allow interruption of the proposed pathological feedback loop responsible for these diseases, improving patient outcomes. Full article

The carotid body (CB) is an interoceptive organ that transmits afferent information to the brain via the carotid sinus nerve (CSN) to maintain homeostasis, i.e., the regulation of internal equilibrium despite external changes. It functions as a complex polymodal receptor capable of sensing multiple stimuli, including blood flow, osmolarity, pO₂, pH, pCO₂, CO₂/H⁺, and temperature. In addition, the CB responds to a wide range of circulating molecules such as angiotensin II, endothelin-1, aldosterone, insulin, histamine, and leptin, and expresses receptors for interleukins (ILs) and tumor necrosis factor-α (TNF-α) (1). CB dysfunction has been associated with conditions such as obstructive sleep apnea (OSA), in which intermittent hypoxemia induces an inflammatory response mediated, among other mechanisms, by reactive oxygen species (ROS). This process contributes to alterations in respiratory drive and enhanced sympathetic nervous system activity. Following streptococcal toxic shock syndrome due to Streptococcus Pyogenes, severe abdominal septic shock, and multiple infectious complications, our patient developed an altered respiratory pattern and a hypercatabolic state that precluded weaning from mechanical ventilation (MV) despite respiratory physiotherapy. Given treatment failure, we hypothesized underlying carotid body (CB) hyperexcitability, likely pre-existing due to obstructive sleep apnea (OSA) and exacerbated by cytokine storm and severe systemic inflammation related to Strept. Pyogenes toxins and subsequent abdominal sepsis from colonic perforation. This may have contributed to sustained sympathetic overactivation and immune dysregulation. Clinically, the patient exhibited increased respiratory drive (30–35 breaths/min), excessive inspiratory effort, and marked patient–ventilator asynchrony in the absence of hypoxemia. Non-targeted physiotherapy may have acted as a second inflammatory hit, perpetuating the inflammatory cycle. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Background: Dynamic risk stratification is fundamental to the modern management of pulmonary arterial hypertension (PAH). However, data on the impact of sequential add-on therapy in patients with Group 1.4 PAH—particularly in Latin American populations—remains limited. This study evaluated changes in risk classification using COMPERA 2.0 and REVEAL Lite 2 scores in patients treated with endothelin receptor antagonist (ERA) and phosphodiesterase type 5 inhibitor (PDE5i) combination therapy (macitentan + sildenafil) at a referral center in Mexico. Methods: In this single-center, retrospective cohort study, 25 patients with a confirmed diagnosis of PAH between 1st January 2022 and 31st December 2024 were evaluated at baseline and after 24 weeks of treatment. Clinical, functional, and biochemical parameters were recorded. Within-patient changes were analyzed using the Wilcoxon signed-rank test, and agreement between risk assessment tools was assessed using Spearman’s correlation coefficient. Results: At 24 weeks, patients demonstrated significant improvement in World Health Organization functional class (p = 0.002) and a significant reduction in brain natriuretic peptide levels (p = 0.003). Both COMPERA 2.0 and REVEAL Lite 2 scores showed a consistent shift toward lower-risk categories. A strong concordance between the two tools was observed. Conclusions: Sequential add-on ERA + PDE5i therapy was associated with meaningful improvement in risk stratification among patients with Group 1.4 PAH. These findings support the clinical utility of simplified, noninvasive risk assessment tools in real-world settings, particularly in resource-constrained environments. Full article

Coronary artery vasospasm (CAV) is a transient, reversible constriction of the epicardial coronary arteries that reduces coronary blood flow and may cause myocardial ischemia. Despite its clinical significance, CAV remains underdiagnosed and can present as chest pain, acute coronary syndrome, malignant arrhythmias or sudden cardiac death. Vasospasm may occur in both angiographically normal coronary arteries and at sites of pre-existing atherosclerotic stenosis. The pathophysiology of CAV is multifactorial and involves vascular smooth muscle cells (VSMCs) hyperreactivity, endothelial dysfunction, chronic inflammation and autonomic dysregulation. VSMCs contraction is mediated by phosphorylation of the myosin light chain (MLC) through calcium (Ca²⁺)/calmodulin-dependent myosin light chain kinase (MLCK), while relaxation is regulated by myosin light chain phosphatase (MLCP). Increased intracellular Ca²⁺ levels and enhanced Ca²⁺ sensitivity contribute to excessive vasoconstriction. Rho-kinase (ROCK) plays a pivotal role in sustained vasospasm by inhibiting MLCP, thereby promoting prolonged smooth muscle contraction. Endothelial dysfunction contributes to CAV by disrupting normal vascular tone regulation, largely as a result of decreased nitric oxide (NO) mediated vasodilation. Chronic low-grade inflammation and oxidative stress exacerbate both endothelial dysfunction and VSMCs contraction. Understanding these molecular mechanisms is essential for identifying novel therapeutic targets. Emerging treatment strategies, including ROCK inhibitors, endothelin receptor antagonists and anti-inflammatory agents, may improve outcomes in patients with refractory CAV. Full article

The endothelin system is critical in chronic kidney disease (CKD) pathogenesis. However, the relative contribution of circulating endothelin-related biomarkers versus genetic variability remains unclear, particularly in diabetic nephropathy (DN) and after kidney transplantation (KTx). This study evaluated plasma concentrations of endothelin-1 (ET-1), endothelin A receptor (ETAR), and anti-ETAR antibodies (ETAR-Ab) in healthy controls, diabetic nephropathy (DN) patients, and DN patients after kidney transplantation (post-KTx). The influence of polymorphisms rs5370 (EDN1) and rs5333 (EDNRA) on endothelin-related parameters was analyzed. Polymorphisms were genotyped via PCR-RFLP, and endothelial-related parameters were determined by ELISA. Significant endothelin system activation was observed in both DN and post-KTx patients. ET-1 and ETAR concentrations were markedly elevated compared to controls, with the highest ET-1 levels detected in the post-KTx group, whereas ETAR-Ab levels were reduced. A sex-specific association for rs5370 was observed in male patients with the TG genotype (a nearly 4.5-fold higher risk of renal replacement therapy than in female patients). In proteinuric DN patients, the TC genotype (rs5333) was associated with elevated ETAR and ETAR-Ab. Endothelin system dysregulation is a prominent and persistent feature of CKD, noted after kidney transplantation. The endothelin activation, observed in transplant patients particularly, highlights the potential clinical relevance of endothelin-related biomarkers and supports the rationale for therapeutic strategies targeting the endothelin pathway, including endothelin receptor antagonists. Full article