Background Chronic obstructive pulmonary disease (COPD) and lung cancer frequently co-occur with shared inflammatory and metabolic drivers, while the systemic role of the renin-angiotensin system (RAS) in this comorbidity remains poorly understood. Methods We integrated Global Burden of Disease, Mendelian randomization, pan-cancer/single-cell transcriptomics, NHANES population data, and functional experiments to dissect this comorbidity, with mechanistic modeling to evaluate lifestyle factors and osteopontin's role in bone marrow mesenchymal stem cell (BMSC) retention and anti-inflammatory signaling. Results GBD analysis demonstrated socioeconomic patterning of COPD-lung cancer burden. Convergent multi-level evidence identified RAS imbalance as a key upstream regulator: the pro-inflammatory ACE/angiotensin II axis was activated while the protective ACE2/angiotensin-(1–7) axis was suppressed, driving immunometabolic reprograming, checkpoint activation, and Th17 inflammation, with coordinated epithelial, immune, and stromal alterations at single-cell resolution. Osteopontin acted as a downstream mediator, promoting BMSC retention via CD44/integrin β 1 interactions and modulating inflammation through PI3K/Akt signaling. Physical activity correlated with balanced RAS activity and lower disease risk. Conclusions We define a RAS–Th17/osteopontin axis as a central regulator of immunometabolic reprograming and tissue repair in COPD-lung cancer comorbidity. These findings support integrated therapeutic strategies targeting RAS, immunometabolism, and BMSC-based repair.
Introduction Prolonged fasting may influence cardiovascular function, but the magnitude and duration dependence of these effects remain unclear. This systematic review and meta-analysis quantified changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) and examined duration-related patterns. Materials and Methods PubMed, Web of Science, and Scopus were searched for human studies reporting pre–post SBP, DBP, and/or HR after prolonged fasting. Hedges’ g and absolute mean differences were pooled using random-effects models. Duration effects were examined using prespecified subgroups (≤3 vs. > 3 days) and cluster-robust meta-regression. Results Twenty-four studies were included. Prolonged fasting reduced SBP (k = 23; g = −0.617; 95% CI, −0.824 to −0.409; mean difference, −8.294 mmHg) and DBP (k = 20; g = −0.435; 95% CI, −0.636 to −0.233; mean difference, −3.982 mmHg), and increased HR (k = 11; g = 0.296; 95% CI, 0.009 to 0.583; mean difference, 3.450 beats·min −1 ). Heterogeneity was high. Between-subgroup differences were significant for SBP and HR but not DBP. Continuous meta-regression identified significant study-level associations between fasting duration and both SBP (β = −0.0547, p = 0.013) and HR (β = 0.1126, p = 0.007), whereas no significant association was observed for DBP (β = −0.0088, p = 0.650). Conclusions Prolonged fasting was associated with lower SBP and DBP and a small increase in HR. Longer fasting duration was associated with greater reductions in SBP and greater increases in HR at the study level, whereas no significant linear association was observed for DBP. These findings should be interpreted cautiously because the meta-regression analyses were exploratory, substantial between-study heterogeneity was present, and study-level associations should not be interpreted as causal duration–response relationships.
Introduction Obesity is a risk factor for infections and severe comorbidities. Patients with obesity infected with dengue virus (DENV) may have a severe course of the disease. This is attributed to several factors, including immunomodulation, endothelial damage, production of pro-inflammatory cytokines, and cellular accumulation of lipids, factors that promote viral replication. Angiotensin II (Ang II) has been linked to obesity and DENV biology, but its role in dengue severity in patients with obesity remains understudied. Method The literature was searched in databases by using the search engines (PubMed, SCOPUS, Web of Sciences, Science Direct, and Google Scholar) Conclusions This review highlights factors present in obesity such as the intracellular lipid droplets, proteins such as MIF (macrophage migration inhibitory factor), and furin (important in DENV replication), presence of chymase (linked to Ang II synthesis), caveolin-1 (related to obesity, dengue, and Ang II) and the different entry receptors of DENV as factors involved in the possible action of Ang II in patients with obesity and dengue. Pro-inflammatory actions of Ang II can increase the inflammatory effects of DENV and the obesity associated chronic inflammatory state, and may be contributing to explain in part the severe progression of dengue in individuals with obesity.
The relationship between kidney dysfunction and the renin angiotensin aldosterone system (RAAS) is known, but limited studies exist on angiotensinogen and relative aldosterone excess across ethnicities and sex groups. We therefore explored cross-sectional and longitudinal associations of kidney function with RAAS components in a population stratified by ethnicity and sex. Materials and methods We included 556 men (Black, n = 283; White, n = 273) and 599 women (Black, n = 293; White, n = 306), with 621 participants followed over 4.9 years. Kidney function was assessed by estimated glomerular filtration rate (eGFR), and Cox regression evaluated whether baseline RAAS components predict lower eGFR (≤25 th percentile) at follow-up. Results At baseline, Black men and women had lower values of RAAS components, including angiotensinogen, and higher eGFR than their White counterparts (all p ≤ 0.016). In cross-sectional analyses, baseline eGFR positively associated with angiotensinogen in White men and women only (all p ≤ 0.036). Lower eGFR at follow-up associated with higher aldosterone to renin ratio (ARR) and lower plasma renin activity and Angiotensin II in Black women only (all p ≤ 0.012). Conclusion In young Black women, higher measures of aldosterone excess relative to renin were associated with a decline in eGFR over time, suggesting potential ethnicity and sex specific influence in aldosterone associated kidney damage.
Background Sarcopenia often occurs alongside metabolic dysfunction-associated steatohepatitis (MASH). The molecular basis of liver-muscle metabolic crosstalk is unclear. Extracellular vesicle (EV)-associated factors and renin-angiotensin system (RAS) signaling modulate systemic metabolic and inflammatory remodeling, yet their involvement in MASH-linked sarcopenia remains uncharacterized. Methods We integrated EV-associated microRNA (miRNA) profiling, bulk and single-cell transcriptomics, weighted gene co-expression network analysis, Mendelian randomization, immune deconvolution, interpretable machine learning, and cellular functional assays to investigate conserved molecular signatures associated with MASH and sarcopenia across liver and skeletal muscle datasets. Results Cross-compartment analysis identified conserved EV-associated miRNA signatures across datasets from liver EVs, circulating EVs and skeletal muscle. Network analysis revealed a RAS regulatory module containing ACE, ACE2 and Hippo kinase MST1. Genetic data associated metabolic liver disease and sarcopenia with RAS-MST1 signatures, while direct causality remained unconfirmed. Single-cell deconvolution showed cell-type-specific enrichment of RAS/MST1 pathways mainly in macrophages, Kupffer cells and regenerative populations. Cellular assays showed that MST1 modulates muscle remodeling-related phenotypes and macrophage polarization in vitro. Interpretable machine learning validated MST1-centric signatures in independent MASH and sarcopenia transcriptomic cohorts. Conclusions This study identifies a candidate EV-associated miRNA-RAS-MST1 network potentially involved in MASH-associated sarcopenia, supports a liver-muscle metabolic crosstalk model, and highlights MST1 as a candidate molecular target for further research.
Background The comparative outcomes of immediate versus staged complete revascularization (CR) in patients with ST-segment–elevation myocardial infarction (STEMI) and multivessel disease remain unclear. Methods We searched the PubMed, Web of Science, EMBASE and Cochrane Library databases until December 11, 2025. The primary endpoints included a composite outcome, all-cause mortality and recurrent MI. We expressed continuous outcome data as mean differences (MDs) and dichotomous outcome data as risk ratios (RRs). Results Eight randomized controlled trials involving 4133 patients were included. Pooled results showed that no significant difference was detected between immediate versus staged CR on the composite outcome (RR,0.91; 95% CI,0.67–1.23;), all-cause mortality (RR,1.33; 95% CI,0.99–1.79) and recurrence MI (RR,0.74; 95% CI,0.50–1.10). ICR did not confer significant differences for individual secondary outcomes (cardiac-cause mortality, repeat revascularization, hospitalization for heart failure, and major bleeding) compared with staged PCI. Additionally, subgroup analyses suggested that treatment effects may vary according to the deferral interval and drug-eluting stent (DES) generation. Conclusions In patients with STEMI and multivessel disease, immediate and staged CR were associated with comparable clinical outcomes. However, the timing of staged PCI and DES generation may influence outcomes.
Background Vascular calcification (VC) is a severe complication of chronic kidney disease (CKD) and increases cardiovascular morbidity and mortality. Extracellular vesicles (EVs) from bone mesenchymal stem cells (BMSCs) may influence vascular health through intercellular communication. This study investigated how CKD alters the anti-calcific function of BMSC-derived EVs, focusing on microRNA content, particularly miR-29a-3p. Methods EVs were isolated from healthy and CKD-affected BMSCs and assessed for size, uptake by vascular smooth muscle cells (VSMCs), and miRNA content. High-phosphate-treated VSMCs and CKD rat models of vascular calcification were used to evaluate the effects of EVs on VC. Circulating miR-29a-3p was measured in hemodialysis patients and correlated with VC severity. Results EVs from both groups showed comparable size and VSMC uptake. However, CKD-derived EVs had an altered miRNA profile, including markedly reduced miR-29a-3p, and showed diminished ability to inhibit phosphate-induced calcification. Restoration of miR-29a-3p suppressed calcification in vitro and in vivo. In hemodialysis patients, circulating miR-29a-3p was inversely associated with calcification severity. Conclusions CKD impairs the anti-calcific function of BMSC-derived EVs partly through downregulation of EV-associated miR-29a-3p. Restoring miR-29a-3p may help mitigate VC in CKD, and circulating miR-29a-3p may serve as a clinical biomarker.
Objective Angiotensin II (Ang II), the principal effector of the renin–angiotensin system, exhibits context-dependent dual roles in cardiovascular and oncological pathophysiology. This review systematically examines the molecular mechanisms underlying its contrasting functions in tissue repair and tumor progression while exploring the clinical translational implications of this functional plasticity. Methods Evidence on Ang II generation pathways, receptor subtype signaling, and downstream molecular networks was synthesized. The analysis focused on how receptor balance, microenvironmental cues, and signaling pathway crosstalk determine biological outcomes. Results In cardiovascular injury, transient low-concentration Ang II preferentially activates the protective AT2R and ACE2/Ang-(1–7)/Mas axes, promoting angiogenesis and anti-inflammatory repair. Conversely, in tumors, chronic hypoxia sustains AT1R activation, triggering Mitogen-activated protein kinase / Extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositol 3-kinase/protein kinase B(PI3 K/AKT), and Hypoxia-inducible factor / Vascular endothelial growth factor (HIF-VEGF) signaling that drive proliferation, EMT, immunosuppression, and therapy resistance. This functional shift depends on receptor subtype ratio, tissue microenvironment characteristics, and signaling node crosstalk. Conclusion Ang II acts as a bifunctional modulator rather than a detrimental factor, with its net effects determined by dynamic regulatory networks. Targeting this duality through receptor-specific strategies, combination immunotherapies, and stage-adaptive interventions may support precision therapeutic approaches for cardiovascular diseases, oncology, and cardio-oncology comorbidities.
Introduction Cardiovascular diseases remain the leading cause of global morbidity and mortality, driven by a complex interplay of inherited and acquired factors that limit the long-term effectiveness of conventional pharmacological, surgical, and device-based therapies. Recent advances in gene therapy have positioned adeno-associated virus (AAV) vectors as a promising platform for addressing the molecular determinants of both inherited and non-inherited cardiac disorders. Owing to their favourable safety profile, low pathogenicity, sustained transgene expression, and broad tissue tropism, AAV vectors have evolved as the most comprehensively evaluated viral delivery system in cardiovascular gene therapy. Method This classical review was compiled after a comprehensive literature search of major scientific databases, including PubMed, Scopus, and Web of Science, using keywords related to adeno-associated virus, therapies, inherited and non-inherited cardiac disorders. This review provides a comprehensive synthesis of the biological properties of AAV vectors, with emphasis on serotype-specific cardiac tropism, receptor usage, immunogenicity, and durability of gene expression. We critically assess preclinical and clinical evidence supporting AAV-mediated gene delivery across a spectrum of cardiac conditions, including heart failure, cardiomyopathies, ischemic heart disease, and inherited arrhythmias, highlighting both therapeutic successes and translational limitations. Conclusions This review highlights the current delivery strategies, genetic cargoes, and emerging genome-editing approaches, which are discussed in the context of efficacy and safety. Key challenges-such as pre-existing immunity, dose-dependent toxicity, off-target transduction, manufacturing scalability, regulatory constraints, and clinical trial design-are analysed to delineate barriers to widespread clinical adoption. Finally, we outline future directions focused on rational capsid engineering, tissue-specific targeting, improved manufacturing pipelines, and optimized clinical strategies required to advance AAV-based gene therapy toward durable and accessible treatments for cardiac diseases.
Introduction Plant-derived extracellular vesicles (PDEVs) are nanoscale lipid bilayer structures secreted by plant cells. As they possess distinctive biological advantages and therapeutic capability, PDEVs have demonstrated their considerable potential in the field of tumor treatment. Methods A systematic literature search was conducted across Web of Science, PubMed, and other databases using terms related to “PDEVs”, “cancer” and “drug delivery”. The studies were comprehensively analyzed to provide the up-to-date biological mechanisms. Results PDEVs exhibit significant anti-cancer functions by inducing cell apoptosis, arresting cell cycle progression, and enhancing anti-tumor immunity. These vesicles serve as efficient delivery platforms for endogenous and exogenous nucleic acids as well as chemotherapeutic drugs, augmenting therapeutic efficacy while reducing off-target toxicity. Emerging insights reveal PDEVs' potential as adjuvants for immunotherapy through modulating gut microbiota and related metabolites. As natural photosensitizers, PDEVs can boost photodynamic therapy efficacy. Furthermore, PDEVs can modulate the renin-angiotensin system (RAS), thereby potentially affecting tumor growth, angiogenesis, and immune responses. Conclusions This review highlights the prospects of PDEVs in cancer therapy by systematically summarizing their intrinsic anti-tumor effects, drug delivery capabilities, and emerging synergistic applications. This work could provide new insights into the clinical translation of PDEVs as a effective anti-cancer strategy, offering new therapeutic options for cancer patients.
Introduction The local hematopoietic bone marrow (BM) renin–angiotensin system (RAS) is a complex network of tissue-specific signaling pathways operating through autocrine, paracrine, and intracrine mechanisms that govern stem cell fate, lineage commitment, and marrow microenvironmental integrity. Neoplastic dysregulation of the local BM RAS drives leukemogenesis through a shift toward the proliferative angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis. The discovery of alamandine and its receptor, Mas-related G protein-coupled receptor D (MrgD), has expanded the non-classical RAS paradigm by introducing a distinct protective signaling branch. Method The alamandine–MrgD axis within the local BM RAS and its role in leukemic transformation was examined and synthesized by searching PubMed/MEDLINE using keywords including alamandine, MrgD receptor, bone marrow renin–angiotensin system, and leukemogenesis. Conclusions The alamandine–MrgD axis exerts anti-proliferative, anti-inflammatory, and antioxidant effects that counterbalance oncogenic ACE/Ang II/AT1R signaling in the hematopoietic marrow microenvironment. This axis functions as an endogenous counter-regulatory component of the BM RAS, modulating cellular proliferation, inflammatory signaling, oxidative stress, and microenvironmental homeostasis during leukemic transformation, positioning it as a critical regulator of physiological hematopoiesis. The biological expression and activity of the alamandine–MrgD axis may serve as both a prognostic biomarker and a therapeutic target in leukemia management.
Aims: Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus (DM) leading to increased morbidity and mortality. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a central role in DCM pathogenesis. Data Synthesis: This narrative review was conducted through a comprehensive literature search of major scientific databases, including PubMed, Scopus, and Web of Science, using keywords related to oxidative stress, inflammation, and diabetic cardiomyopathy. Peer-reviewed experimental and translational studies were critically analyzed and synthesized to elucidate key molecular mechanisms. Conclusions: This review highlights the molecular interplay between oxidative stress and inflammatory pathways—including Nrf2, NF-κB, and Sirt1 signaling—in promoting myocardial fibrosis, apoptosis, and dysfunction. Furthermore, therapeutic strategies targeting oxidative stress and inflammation, such as natural antioxidants and Nrf2 activators, show promise in mitigating DCM progression. Understanding these mechanisms provides new insights into potential interventions to prevent and treat diabetic heart disease.
Introduction Infectious diseases caused by pathogens have posed health concerns worldwide since ancient times, and the development of preventive approaches has been a focus. Pathogens establish infections by targeting particular host protein receptors, such as angiotensin-converting enzyme-2 (ACE2), membrane-anchored proteins, or signaling components like G-protein-coupled receptors (GPCRs), through interactions or by modulating host proteins via secreted toxic compounds. GPCRs are broadly distributed receptors regulating multiple physiological activities, from neurotransmitter feedback and environmental triggers to hormonal feedback. Innumerable pathogens target 100 of the GPCRs in different ways to evade immune responses, survival, and virulence. Method For the synthesis of this review, the literature was searched in databases by using the search engines (like PubMed, SCOPUS, Web of Sciences, ScienceDirect, Google Scholar, etc.), and the following keywords: “Infectious Diseases, G-protein coupled receptors (GPCRs), angiotensin converting enzyme-2 (ACE-2), Pathophysiology, Renin-angiotensin-aldosterone system (RAAS)” were used. Conclusions This focused review emphasizes the roles of GPCR and ACE2 receptors in the RAAS, pathophysiology of infectious diseases, and their impact on these receptor-mediated downstream signaling pathways. The current article also discussed the impact of GPCRs and ACE2 receptors on pathogenicity and host cellular responses, and on improving our knowledge of host-pathogen interactions at the molecular and cellular levels; therefore, it might open avenues for novel therapeutic agents and preventive approaches.
Introduction: Thoracic aortic aneurysm (TAA) is a life-threatening aortic disease often referred to as a “silent killer” because it progresses insidiously until reaching a critical stage, when aortic dissection or rupture may occur. The pathophysiology of TAA involves complex and dysregulated interactions between vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM), driven by genetic mutations, mechanical stress, inflammatory responses, and oxidative stress. However, the causal relationships and molecular links among these processes remain incompletely understood. Recently, microRNAs (miRNAs), a class of endogenous non-coding RNAs of approximately 22 nucleotides that regulate gene expression, have attracted increasing attention in TAA because of their remarkable stability, tissue specificity, and regulatory versatility, as well as their potential roles in both disease pathogenesis and biomarker development. Methods: A systematic literature search was conducted across Web of Science, PubMed, and other relevant databases using keywords related to TAA, microRNAs, VSMCs, ECM remodeling, pathogenesis, and biomarker. The retrieved studies were synthesized to examine miRNA-mediated regulation of VSMC dysfunction and ECM remodeling as a central mechanistic framework for TAA initiation and progression, while also integrating upstream drivers such as genetic alterations and mechanical stress, as well as modulatory processes including inflammation, oxidative stress, and endothelial-to-mesenchymal transition (EndMT). The translational potential of miRNAs as biomarkers and therapeutic targets, together with the key challenges to their clinical application, was also evaluated. Results: Current evidence indicates that miRNAs act as critical molecular regulators linking upstream pathogenic drivers, including genetic abnormalities and mechanical stress, to key downstream processes such as VSMC dysfunction, ECM remodeling, inflammation, oxidative stress, and EndMT. These interconnected mechanisms do not operate independently but rather interact and reinforce one another, thereby promoting aneurysm initiation and progression. In addition, a growing body of evidence suggests that TAA-related miRNAs may serve as promising biomarkers for early diagnosis and prognostic assessment, while also representing potential therapeutic targets. Conclusions: This review highlights the multifaceted roles of miRNAs in TAA and supports their value as an integrative framework for understanding disease pathogenesis. Although miRNAs show considerable promise as biomarkers and therapeutic targets, their clinical translation remains limited by heterogeneity, lack of standardization, and insufficient large-scale validation. Future efforts should focus on multicenter validation and integration with imaging and clinical data to advance the use of miRNAs in precision diagnosis and management of TAA.
Background Kawasaki disease is an acute pediatric vasculitis and a leading cause of coronary artery lesions. Despite immunoglobulin therapy, some patients develop progressive coronary injury, yet mechanisms linking immune activation, metabolic remodeling, and renin-angiotensin-aldosterone system-mediated vascular inflammation remain unclear. Methods We applied an integrative multi-omics approach combining bulk and single-cell transcriptomics, genetic association, Mendelian randomization, and molecular docking. Systems analyses, including gene set enrichment and co-expression networks, were used to identify disease-associated pathways and genetic signals related to disease susceptibility. Results We identified an S100A8/A9-ACE-angiotensin axis that integrates immune activation, metabolic remodeling, and vascular inflammation in Kawasaki disease. Genetic analyses suggested that genetically predicted increases in S100A9 and ACE expression were associated with higher Kawasaki disease susceptibility. This axis was upregulated in patients with coronary lesions. Molecular docking identified computationally favorable binding poses among angiotensin, S100A proteins, and ACE, providing structural hypotheses that require biochemical and cellular validation. Conclusion The S100A8/A9-ACE-angiotensin axis may represent an important regulatory axis associated with coronary injury in Kawasaki disease. This RAAS-centered immune-metabolic-vascular framework identifies candidate biomarkers for coronary risk stratification and may guide future therapeutic evaluation in high-risk Kawasaki disease.
Childhood depression has become an increasingly significant issue in global public health. While traditional medication and counseling are commonly used, non-pharmacological interventions are gaining popularity due to the limitations of conventional approaches. This research explores the potential benefits of exercise, music therapy, and dance therapy in treating childhood depression, with a particular focus on the renin-angiotensin system (RAS) and its role in mood regulation. The RAS, which regulates blood pressure and fluid balance, is linked to various mood disorders, including depression. Regular physical activity can help reduce stress levels, enhance serotonin balance, and regulate the norepinephrine-angiotensin system. Dance therapy, through repetitive movements, fosters personal expression and reduces communication barriers. Studies indicate that structured exercise can significantly alleviate depression, and group-based music and dance interventions are especially beneficial for socially withdrawn children. Future efforts should focus on enhancing multidisciplinary collaboration, integrating these therapies into educational programs, and developing more targeted interventions. Schools have a key role in ensuring that these interventions are accessible, feasible, and effectively implemented, helping create a comprehensive support system for children's physical and mental well-being.
The renin–angiotensin system (RAS) plays a pivotal role in the initiation and progression of hepatocellular carcinoma (HCC). Through its regulation of angiogenesis, tissue fibrosis, and immune cell activity, RAS profoundly shapes the tumor microenvironment (TME), thereby promoting tumor growth and metastasis. Activation of RAS enhances tumor vascularization while concurrently suppressing anti-tumor immune responses, contributing to immune evasion. Preclinical studies have demonstrated that RAS inhibitors can counteract these pro-tumorigenic processes by remodeling the TME and enhancing immune cell infiltration. Our summary indicates that treatment with RAS inhibitors synergizes with immune checkpoint blockade, markedly strengthening anti-tumor immunity and improving therapeutic efficacy in experimental models. Although the clinical benefits of RAS inhibitors as monotherapy remain limited, their integration with immunotherapy, targeted agents, or anti-angiogenic therapies has revealed considerable synergistic potential. Future research should aim to elucidate the precise mechanisms by which RAS regulates immune modulation in HCC and to optimize combination regimens that enable more effective and personalized therapeutic strategies for patients.
Background The Angiotensin-(1-7)/MAS1 axis mediates cardioprotection, but its regulation under hypoxia, aging, and hypertension remains unclear. MicroRNAs (miRNAs) are key modulators of cardiovascular signaling, yet the role of miR-6315 in MAS1 regulation is unknown. Objective To investigate how hypoxic preconditioning regulates the miR-6315-MAS1 axis and its role in cardiomyocyte survival under Angiotensin II (Ang II) stress and pathological conditions. Methods Rat H9c2 and human AC16 cardiomyocytes were exposed to normoxia or hypoxia (0.5-24 h). MAS1 targeting by miR-6315 was validated using dual-luciferase assays. Gene and protein expression were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence. In vivo, Wistar-Kyoto and spontaneously hypertensive rats were subjected to graded hypoxia and aging models. Results Hypoxic preconditioning induced transient MAS1 upregulation, with increased protein kinase B (AKT) activation and hypoxia-inducible factor-1 alpha (HIF1 alpha) stabilization. miR-6315 directly suppressed MAS1, whereas its inhibition restored survival signaling. Ang II increased miR-6315 and apoptosis, effects attenuated by hypoxia. Aging and hypertension were associated with reduced MAS1 expression. Conclusion Hypoxic preconditioning transiently relieves miR-6315-mediated repression of MAS1, activating a cardioprotective pathway that may represent a therapeutic target for enhancing myocardial resilience.
Introduction: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), yet effective disease-modifying therapies remain limited. Emerging evidence implicates long non-coding RNAs (lncRNAs) in the pathogenesis of DN, but the functional relevance of plasmacytoma variant translocation 1 (PVT1) and its downstream mechanism remain poorly defined. Here, we investigated whether PVT1 protects against diabetic renal injury through the miR-423-5p/Sirt1/HIF-1 alpha axis. Materials and Methods: DN was modeled in db/db mice and high glucose-treated renal cells. PVT1 was overexpressed or inhibited, and miR-423-5p was modulated using specific mimics or inhibitors. Renal function, histopathology, and fibrotic changes were evaluated by biochemical assays, histological staining, qRT-PCR, and Western blotting. The expression of PVT1, miR-423-5p, Sirt1, HIF-1 alpha, and fibrosis-related markers was determined to define their regulatory relationships. Results: PVT1 was dysregulated in diabetic kidneys and high glucose-exposed renal cells. In db/db mice, PVT1 overexpression significantly improved renal function, as evidenced by reduced 24-h urinary protein excretion, serum creatinine, and blood urea nitrogen, and attenuated pathological renal injury. PVT1 also suppressed extracellular matrix accumulation and fibrosis-related signaling, including alpha-SMA, collagen I, collagen IV, fibronectin, and TGF-beta 1. Mechanistically, PVT1 acted through the miR-423-5p/Sirt1/HIF-1 alpha pathway, and inhibition of miR-423-5p abrogated the renoprotective effects of PVT1. These findings support a functional model in which PVT1 alleviates diabetic renal injury by repressing miR-423-5p and restoring Sirt1-dependent signaling. Conclusions: PVT1 mitigates DN progression by targeting the miR-423-5p/Sirt1/HIF-1 alpha axis and limiting renal fibrosis. This lncRNA-centered regulatory pathway may represent a promising therapeutic target for diabetic kidney disease.
