Acute kidney injury (AKI) remains a critical condition with substantial morbidity and mortality in hospitalized patients. Emerging research has underscored the protective role of SIRT6 in kidney diseases through diverse signaling pathways. Our current report aimed to elucidate the mechanisms by which SIRT6 mitigated the progression of AKI. Immunohistochemical and Oil Red O staining techniques were employed to assess the expression of SIRT6 and lipid metabolism in both AKI patients and AKI mice treated with UBCS039, a specific SIRT6 activator (30 mg/kg, i.p.). Kidney tissues from AKI mice were analyzed using LC-MS/MS to uncover SIRT6-related signaling pathways involved in AKI. Additionally, human proximal renal tubule cells (HK-2) were exposed to UBCS039 or transfected pcDNA3.1-SIRT6 overexpression plasmid to investigate the underlying signaling mechanisms of SIRT6 on lipid metabolism using Western blotting analysis and Oil Red O staining. Gene expression levels of ACMSD was detected by qRT-PCR and Western blotting in HK-2 cells. Dual-luciferase reporter assay was used to verify the effect of SIRT6 on regulating ACMSD transcription. Our findings revealed a significant reduction in SIRT6 expression in both AKI patients and AKI mice. Treatment with UBCS039, however, significantly decreased lipid accumulation and apoptosis in AKI mice. Proteomic analysis and Dual-luciferase reporter assay identified ACMSD as a downstream target of SIRT6. In vitro studies further demonstrated that SIRT6 enhanced lipid metabolism and mitigated apoptosis through the inhibition of ACMSD expression. This study demonstrated that SIRT6 promoted lipid metabolism by inhibiting the ACMSD pathway, thereby reducing apoptosis in AKI. These findings suggested that targeting ACMSD could offer a novel therapeutic strategy for SIRT6-mediated intervention in AKI.

Sepsis-induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin-1 (ET-1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET-1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET-1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis-induced acute cardiorenal injuries. To analyse the role of ET-1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non-treated group, CLP-treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham-operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET-1, IL-6, and lactate were measured. The expression of TNF-α, p38, Klotho, and caspase-3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET-1, IL-6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF-α and caspase-3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE-i) phosphoramidon, are promising agents against sepsis-induced organ damage. This was evident in their cardiorenal protective effects, up-regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.

Pannexin 1 (Panx1) is a membrane-associated channel that, when activated, facilitates the release of small metabolites into the extracellular environment. These metabolites signal as damage-associated molecular patterns (DAMP) and initiate inflammation. Upregulation and activation of Panx1 is one of the early events during inflammatory injury. Animal models show that a lack of Panx1 is protective against acute kidney injury (AKI). How Panx1 modulates AKI is poorly understood. We utilized both in vivo and in vitro models of PANX1 overexpression to study mitochondrial function, cell death, and inflammation to evaluate how Panx1 contributes to AKI. We used two models of AKI, ischemia-reperfusion injury (IRI) and cisplatin-induced AKI (cis-AKI), in animals that overexpress PANX1 globally or specifically in the proximal tubule or in the endothelium. Cisplatin-induced injury was investigated in vitro in PANX1-overexpressing proximal tubule cells in culture. Both global and proximal tubule-specific overexpression of PANX1 exacerbated AKI, whereas endothelium-specific overexpression had no effect. Panx1-dependent metabolite release and alterations in the intracellular compartment in proximal tubules independently contributed to cell death in vitro. PANX1 overexpression impaired mitochondrial function and increased mitochondrial reactive oxygen species (ROS) production. PANX1 overexpression resulted in increased inflammation in the kidneys during cis-AKI. We showed that PANX1 overexpression resulted in overt renal injury during AKI that is in part mediated by reduced mitochondrial function, increased cell death, and inflammation. Selective strategies to inhibit Panx1 could help prevent or treat AKI.NEW & NOTEWORTHY Despite the huge medical, economical, and quality of life burden that AKI poses to patients, there are no Food and Drug Administration (FDA)-approved therapeutic or pharmaceutical interventions for AKI. Pannexin 1 (Panx1), which is upregulated in patients with AKI as well as in animals that develop experimental AKI, plays a crucial role in mediating both inflammation and cell death during AKI. Our findings suggest clinical interventions with molecules that inhibit Panx1 channel activity could improve outcomes in AKI patients.

Sepsis-induced acute kidney injury (S-AKI) is a life-threatening complication of sepsis, marked by dysregulated inflammation, metabolic derangements, and immune dysfunction, driving high mortality. Its multifactorial pathogenesis increasingly implicates DNA methylation-a core epigenetic mechanism-as a critical disease modulator. This review synthesizes current knowledge of DNA methylation in S-AKI, covering molecular mechanisms, cellular dysfunction, and translational potential. In immune cells, sepsis-induced aberrant DNA methylation promotes hypomethylation of pro-inflammatory genes and hypermethylation of anti-inflammatory loci, exacerbating cytokine storms and immunosuppression. In renal tubular epithelial cells, abnormal methylation disrupts apoptosis, oxidative stress responses, and mitochondrial bioenergetics, impairing repair and accelerating S-AKI progression. Renal vascular endothelial cells exhibit methylation-dependent dysregulation of vasoactive and inflammatory pathways, compromising microvascular homeostasis and renal hemodynamics. DNA methylation signatures offer promise as early S-AKI biomarkers, with cell-type-specific patterns reflecting severity, injury, and prognosis. Targeting DNA methyltransferases with epigenetic modifiers represents a novel therapy, though challenges arise from sepsis's complex epigenetic landscape-bidirectional methylation changes, histone crosstalk, and context-dependent responses. A key paradox lies in DNA methylation's dual traits: stability underpinning biomarker reliability and plasticity enabling dynamic inflammatory adaptation, yet introducing therapeutic heterogeneity. Future research should prioritize dissecting cell-specific methylation mechanisms, integrating multi-omics to identify epigenetic subnetworks, and developing real-time monitoring tools for precision diagnosis and tailored interventions. Advancing these frontiers may translate epigenetic insights into transformative strategies to improve outcomes for this devastating condition.

Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.

Sepsis-associated acute kidney injury (AKI) presents a significant clinical challenge, necessitating the identification of predictive indicators for early detection and intervention. This retrospective case-control study aimed to investigate the predictive potential of renal vascular resistance index and serum biomarkers in sepsis-associated AKI.

A cohort of 108 patients diagnosed with sepsis was separated into two groups-those with acute kidney injury (AKI) and those without-using the diagnostic criteria established by the kidney disease: Improving Global Outcomes (KDIGO) guidelines. Various demographic, clinical, and laboratory parameters were collected, including renal resistive index, serum biomarkers, disease severity scores, and clinical outcomes. Statistical analyses, including t-tests, correlation analysis, receiver operating characteristic (ROC) analysis, and joint model construction, were conducted to evaluate the predictive value of these parameters.

The AKI group exhibited higher APACHE II and SOFA scores compared to the non-AKI group, indicating the association between disease severity scores and the presence of AKI in septic patients. Renal resistive index and several serum biomarkers, including C-reactive protein and procalcitonin, were notably elevated in the AKI group. Correlation analysis demonstrated significant associations between renal vascular resistance index, serological biomarkers, and clinical severity scores. ROC analysis revealed that several parameters, including Renal Resistive Index (AUC = 0.667), C-reactive Protein (CRP, AUC = 0.665), Platelet Count (AUC = 0.666), and Prothrombin Time (AUC = 0.669), demonstrated moderate diagnostic performance for predicting sepsis-associated AKI. These parameters were subsequently incorporated into a joint predictive model, which exhibited robust diagnostic accuracy with an AUC of 0.780, highlighting its potential utility as a reliable predictive tool in clinical practice.

The study findings underscore the potential for integrating renal vascular parameters and serum biomarkers in clinical risk stratification and early intervention strategies for sepsis-associated AKI.

Not applicable.

Sepsis-induced acute kidney injury (S-AKI) is a common complication of sepsis. It occurs at high incidence and is associated with a high level of mortality in the intensive care unit (ICU). The pathophysiologic mechanisms underlying S-AKI are complex, and include renal vascular endothelial cell dysfunction. The endothelial glycocalyx (EG) is a polysaccharide/protein complex located on the cell membrane at the luminal surface of vascular endothelial cells that has anti-inflammatory, anti-thrombotic, and endothelial protective effects. Recent studies have shown that glycocalyx damage plays a causal role in S-AKI progression. In this review, we first describe the structure, location, and basic function of the EG. Second, we analyze the underlying mechanisms of EG degradation in sepsis and S-AKI. Finally, we provide a summary of the potential therapeutic strategies that target the EG.

Sepsis, characterized by immune dysregulation, inflammatory cascades, and coagulation dysfunction, remains a global health challenge with high mortality, particularly in patients with multiple organ dysfunction syndrome (MODS). Existing prognostic tools, such as SOFA and APACHE II scores, are limited by complexity and lack of real-time monitoring, necessitating simple and reliable biomarkers for risk stratification and individualized management.

This study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte-to-platelet ratio (NLPR) for mortality in sepsis patients and explore its potential utility in dynamic risk stratification and treatment optimization.

We conducted a retrospective cohort study using the MIMIC-IV database (v3.1), including adult sepsis patients meeting Sepsis-3.0 criteria. NLPR was calculated based on neutrophil, lymphocyte, and platelet counts within 24 h of admission. Patients were stratified into quartiles (Q1-Q4) based on NLPR values. Kaplan-Meier survival analysis, Cox regression models, and restricted cubic spline (RCS) analysis were performed to assess NLPR's association with 28-day, 90-day, and 365-day mortality. Subgroup analyses examined NLPR's performance in diverse clinical populations.

NLPR was a strong and independent predictor of mortality at all time points. Patients in the highest NLPR quartile (Q4) had significantly higher 28-day (28.22% vs. 12.64%), 90-day (36.82% vs. 18.06%), and 365-day (44.94% vs. 25.58%) mortality compared to the lowest quartile (Q1, all P < 0.001). Cox regression confirmed the independent association of high NLPR with mortality after adjusting for confounders such as age, gender, BMI, and SOFA scores. RCS analysis identified nonlinear relationships between NLPR and mortality, with critical thresholds (e.g.,NLPR = 6.5 for 365-day mortality) providing actionable targets for early risk identification. Subgroup analysis revealed consistent predictive performance across clinical populations, with amplified risks in younger patients, malnourished individuals, and those with acute kidney injury.

NLPR is a simple, accessible, and robust biomarker for sepsis risk stratification, integrating inflammation and coagulation data. It complements traditional scoring systems, provides actionable thresholds for early intervention, and facilitates dynamic monitoring. These findings underscore NLPR's potential to improve clinical decision-making and outcomes in sepsis management, warranting validation in prospective multicenter studies.

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.

Acute kidney injury (AKI) is a clinical challenge characterized by elevated morbidity and a substantial impact on individual health and socioeconomic factors. A comprehensive examination of the molecular pathways behind AKI is essential for its prevention and management. In recent years, vigorous research in the domain of AKI has concentrated on pathophysiological characteristics, early identification, and therapeutic approaches across many aetiologies and highlighted the principal themes of oxidative stress, inflammatory response, apoptosis, necrosis, and immunological response. This review comprehensively reviewed the molecular mechanisms underlying AKI, including oxidative stress, inflammatory pathways, immune cell-mediated injury, activation of the renin-angiotensin-aldosterone (RAAS) system, mitochondrial damage and autophagy, apoptosis, necrosis, etc. Inflammatory pathways are involved in the injuries in all four structural components of the kidney. We also summarized therapeutic techniques and pharmacological agents associated with the aforementioned molecular pathways. This work aims to clarify the molecular mechanisms of AKI thoroughly, offer novel insights for further investigations of AKI, and facilitate the formulation of efficient therapeutic methods to avert the progression of AKI.

The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators. Endothelial dysfunction (ED), characterized by impaired vasodilation, inflammation, and thrombosis, triggers future cardiovascular (CV) diseases. Chronic kidney disease, a state of chronic inflammation caused by oxidative stress, metabolic abnormalities, infection, and uremic toxins damages the endothelium. ED is also associated with a decline in estimated glomerular filtration rate. After kidney transplantation, endothelial functions undergo immediate but partial restoration, promising graft longevity and enhanced CV health. However, the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED, culminating in poor CV health and graft survival. ED in kidney transplant recipients is an under-recognized and poorly studied entity. CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts. ED contributes to the pathogenesis of many of the CV diseases. Various biomarkers and vasoreactivity tests are available to study endothelial functions. With an increasing number of transplants happening every year, and improved graft rejection rates due to the availability of effective immunosuppressants, the focus has now shifted to endothelial protection for the prevention, early recognition, and treatment of CV diseases.

TAFRO syndrome, entailing thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly, was previously considered a subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO), with the diagnosis requiring pathology supporting Castleman disease. However, lymph node biopsies may be difficult for TAFRO patients (TAFRO without pathological evidence: TAFRO-w/op-iMCD), and sometimes these biopsies do not confirm iMCD (TAFRO-w/o-iMCD). We aimed to compare the clinical features and prognosis of TAFRO subgroups.

We retrospectively analyzed the cases of 50 iMCD-TAFRO and 11 TAFRO-w/o-iMCD patients treated from May 2015 to April 2024.

The groups showed no significant differences in clinical presentation or laboratory data. Both groups of patients were treated with iMCD-targeted strategies addressing cytokine storms. With a median follow-up of 21.4 (range: 0.5-107.0) months, there were no significant differences between iMCD-TAFRO and TAFRO-w/o-iMCD patients in 3-month response rate (72.1% vs. 88.9%, p=0.525), 6-month response rate (70.0% vs. 83.3%, p=0.849), or best overall response rate (77.6% vs. 90.0%, p=0.645). The estimated 3-year progression-free survival rate (65.8% vs. 90.0%, log-rank p=0.163) and the estimated 3-year overall survival rate (77.0% vs. 100%, log-rank p=0.145) were also not significantly different. Cox univariate analysis showed that decreased estimated glomerular filtration rate (<60 mL/min/1.73 m2) was associated with an increased risk of disease progression (hazard ratio: 4.133, 95% confidence interval: 1.561-10.940, p=0.004).

iMCD-TAFRO and TAFRO-w/o-iMCD could be considered overlapping entities and these patients should be treated promptly, targeting cytokine storms with similar strategies for each group of patients.

G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.

Narciclasine (Ncs) was effective in sepsis management due to its antioxidant properties. The present study dissected the protective effects of Ncs against sepsis-associated acute kidney injury (SA-AKI) and the molecular mechanisms. The SA-AKI mice were developed using cecum ligation and puncture and pretreated with Ncs and adenoviruses. Human renal microvascular endothelial cells (RMECs) were induced with LPS and treated with Ncs. Ncs alleviated proximal tubular dilatation, interstitial widening, and necrosis in renal tissues and reduced the renal injury marker and pro-inflammatory cytokine levels in the serum of SA-AKI mice. Ncs promoted the expression of ZO-1, VE-cadherin, and CD31 and the activities of SOD, GSH-Px, and CAT, and inhibited the levels of pro-inflammatory cytokines, and apoptosis rate in LPS-treated RMECs. Estrogen receptor 1 (ESR1) was a target protein of Ncs, and S100 calcium-binding protein A11 (S100A11) was a target of the transcription factor ESR1. Ncs blocked transcription of S100A11 by inhibiting ESR1. Silencing of S100A11 overturned the deteriorating effects of ESR1 overexpression on SA-AKI progression in vivo and RMEC injury in vitro. These findings suggest that Ncs may ameliorate SA-AKI by repressing the ESR1/S100A11 signaling, providing a novel perspective for research on SA-AKI.

Sepsis-related organ dysfunction is associated with increased morbidity and mortality. Previous studies have found that the endothelium plays crucial roles in maintaining the vascular permeability during sepsis, as well as in regulating inflammation and thrombosis. During sepsis, endothelial cells may release cytokines, chemokines, and pro-coagulant factors, as well as express adhesion molecules. In general, endothelial responses during sepsis typically inhibit bacterial transmission and coordinate leukocyte recruitment to promote bacterial clearance. However, excessive or prolonged endothelial activation can lead to impaired microcirculation, tissue hypoperfusion, and organ dysfunction. Given the structural and functional heterogeneity of endothelial cells in different organs, there are potential differences in endothelial responses by organ type, and the risk of organ damage may vary accordingly. This article reviews the endothelial response observed in sepsis and its effects on organ function, summarizes current progress in the development of therapeutic interventions targeting the endothelial response, and discusses future research directions to serve as a reference for researchers in the field.

The role of BMAL1 in various diseases remains unclear, particularly its impact on sepsis-induced acute kidney injury (AKI). This study aims to investigate the role of BMAL1 in sepsis-induced AKI and its potential effects on cell ferroptosis. Initially, we assessed BMAL1 expression levels in mice treated with sepsis-induced AKI (via LPS injection) and in LPS-stimulated renal tubular epithelial cells. Subsequently, we explored the correlation between BMAL1 and ferroptosis using sequencing technology, validating our findings throughout experimental approaches. To further elucidate BMAL1's specific effects on AKI-related ferroptosis, we constructed BMAL1 overexpression models in mice and cells, analysing its impact on AKI and ferroptosis both in vivo and in vitro. Furthermore, using transcriptome sequencing technology, we identified key BMAL1-regulated genes and their associated biological pathways, validating these findings through in vivo and in vitro experiments.

Our findings indicate decreased BMAL1 expression in sepsis-induced AKI. BMAL1 overexpression effectively mitigated renal tubular injury by reducing ferroptosis levels in renal tubular epithelial cells. Using transcriptome sequencing and ChIP-qPCR technology, we identified YAP as a target of BMAL1. The overexpression of BMAL1 significantly reduced the transcriptional activity of YAP and inhibited the Hippo signalling pathway. Treatment with the Hippo inhibitor Verteporfin (VP) reversed the BMAL1-downregulation-induced damage. Additionally, our study revealed that YAP positively regulates ACSL4 gene expression and its downstream signalling pathways.

This study demonstrates that BMAL1 overexpression alleviates renal tubular epithelial cell injury and ferroptosis by inhibiting YAP expression and the Hippo pathway, thereby exerting protective effects in sepsis-induced AKI. These findings underscore the therapeutic potential of targeting BMAL1 in managing sepsis-induced AKI.

Sepsis-induced acute kidney injury (SI-AKI) is a common clinical syndrome that is associated with high mortality and morbidity. Effective timely detection may improve the outcome of SI-AKI. Kidney-derived cell-free DNA (cfDNA) may provide new insight into understanding and identifying SI-AKI. Plasma cfDNA from 82 healthy individuals, 7 patients with sepsis non-acute kidney injury (SN-AKI), and 9 patients with SI-AKI was subjected to genomic methylation sequencing. We deconstructed the relative contribution of cfDNA from different cell types based on cell-specific methylation markers and focused on exploring the association between kidney-derived cfDNA and SI-AKI.Based on the deconvolution of the cfDNA methylome: SI-AKI patients displayed the elevated cfDNA concentrations with an increased contribution of kidney epithelial cells (kidney-Ep) DNA; kidney-Ep derived cfDNA achieved high accuracy in distinguishing SI-AKI from SN-AKI (AUC = 0.92, 95% CI 0.7801-1); the higher kidney-ep cfDNA concentrations tended to correlate with more advanced stages of SI-AKI; strikingly, SN-AKI patients with potential kidney damage unmet by SI-AKI criteria showed higher levels of kidney-Ep derived cfDNA than healthy individuals. The autonomous screening of kidney-Ep (n = 24) and kidney endothelial (kidney-Endo, n = 12) specific methylation markers indicated the unique identity of kidney-Ep/kidney-Endo compared with other cell types, and its targeted assessment reproduced the main findings of the deconvolution of the cfDNA methylome. Our study first demonstrates that kidney-Ep- and kidney-Endo-specific methylation markers can serve as a novel marker for SI-AKI emergence, supporting further exploration of the utility of kidney-specific cfDNA methylation markers in the study of SI-AKI.

Angiopoietin-2, an important contributor to angiogenesis and vascular remodeling, is increasingly recognized in kidney research. This review explores clinical insights and experimental perspectives on angiopoietin-2 in kidney diseases. Traditionally seen as an antagonist of the Tie-2, which is a receptor tyrosine kinase of endothelial cells and some hematopoietic stem cells, angiopoietin-2 exerts both proangiogenic and antiangiogenic effects, making it a versatile and context-dependent player in kidney pathophysiology. Elevated circulating angiopoietin-2 levels in clinical scenarios are associated with sepsis and acute kidney injury (AKI), emphasizing its role as a biomarker of disease severity. In diabetic kidney disease, circulating angiopoietin-2 correlates with albuminuria, a crucial indicator of disease progression, and may serve as a treatment target in protecting the endothelium. Angiopoietin-2 is implicated in chronic kidney diseases (CKDs), where its elevated circulating levels correlate with kidney outcomes and cardiovascular complications, suggesting its potential impact on kidney function and overall health. In experimental settings, angiopoietin-2 plays a pivotal role in angiogenesis and lymphangiogenesis, influencing vascular stability and endothelial integrity. The context-dependent agonist and antagonist role of angiopoietin-2 is regulated by a Tie-2 phosphatase, vascular endothelial protein tyrosine phosphatase (VEPTP), further underscoring its complexity. Angiopoietin-2 is also involved in regulating cellular integrity, inflammation, and endothelial permeability, making it a promising therapeutic target for conditions characterized by disrupted endothelial junctions and vascular dysfunction. This review provides a comprehensive overview of the diverse roles of angiopoietin-2 in kidney research, offering insights into potential therapeutic targets and advancements in managing kidney diseases.

Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and mitogen-activated protein kinase (MAPK) c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 h after CLP sepsis initiation. E-selectin, not vascular cell adhesion molecule-1 (VCAM-1), was expressed in glomeruli at the same time point. In a subset of mice at 72 h after CLP sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 h after CLP sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment.

Acute kidney injury (AKI) is a common complication of traumatic hemorrhagic shock. The risk factors for AKI after traumatic hemorrhagic shock remain unclear. The aim of this study was to investigate the risk factors for AKI after traumatic hemorrhagic shock.

This was a ten-year retrospective cohort study of patients who experienced traumatic hemorrhagic shock between January 2013 and April 2023. Patient characteristics and clinical data were recorded for 417 patients. The outcome was the occurrence of AKI, defined as a serum creatinine increase of ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 h, or an increase to 1.5 times the baseline, or a urine volume of < 0.5 mL/(kg h.). Risk factors for AKI were tested by logistic regression models.

The incidence of AKI after traumatic hemorrhagic shock was 29.3% (122/417 patients). Multivariable analysis revealed that the independent risk factors for AKI included age (OR, 1.048; 95% CI, 1.022-1.074; p < 0.001), B-type natriuretic peptide (OR, 1.002; 95% CI, 1.000-1.004; p = 0.041), sepsis (OR, 4.536; 95% CI, 1.651-12.462; p = 0.030) and acute myocardial injury (OR, 2.745; 95% CI, 1.027-7.342; p = 0.044). Road traffic accidents (OR, 0.202; 95% CI, 0.076-0.541; p = 0.001), mean arterial pressure (OR, 0.972; 95% CI, 0.950-0.995; p = 0.017), and base excess (OR, 0.842; 95% CI, 0.764-0.929; p = 0.001) were negatively correlated with AKI. The area under the receiver operating characteristic (ROC) curve for prediction by this model was 0.85 (95% CI, 0.81-0.90).

The incidence of AKI after traumatic hemorrhagic shock was 29.3% in our series. Indicators of blood perfusion, sepsis and acute myocardial injury may be independent risk factors for AKI after traumatic hemorrhagic shock. Early detection and effective intervention on these risk factors could reduce the occurrence of AKI and improve outcomes.

The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

Contrast-induced acute kidney injury (CIAKI) is a common complication with limited treatments. Intermedin (IMD), a peptide belonging to the calcitonin gene-related peptide family, promotes vasodilation and endothelial stability, but its role in mitigating CIAKI remains unexplored. This study investigates the protective effects of IMD in CIAKI, focusing on its mechanisms, particularly the cAMP/Rac1 signaling pathway. Human umbilical vein endothelial cells (HUVECs) were treated with iohexol to simulate kidney injury in vitro. The protective effects of IMD were assessed using CCK8 assay, flow cytometry, ELISA, and Western blotting. A CIAKI rat model was utilized to evaluate renal peritubular capillary endothelial cell injury and renal function through histopathology, immunohistochemistry, immunofluorescence, Western blotting, and transmission electron microscopy. In vitro, IMD significantly enhanced HUVEC viability and mitigated iohexol-induced toxicity by preserving intercellular adhesion junctions and activating the cAMP/Rac1 pathway, with Rac1 inhibition attenuating these protective effects. In vivo, CIAKI caused severe damage to peritubular capillary endothelial cell junctions, impairing renal function. IMD treatment markedly improved renal function, an effect negated by Rac1 inhibition. IMD protects against renal injury in CIAKI by activating the cAMP/Rac1 pathway, preserving peritubular capillary endothelial integrity and alleviating acute renal injury from contrast media. These findings suggest that IMD has therapeutic potential in CIAKI and highlight the cAMP/Rac1 pathway as a promising target for preventing contrast-induced acute kidney injury in at-risk patients, ultimately improving clinical outcomes.

Sepsis-associated acute kidney injury (AKI) is a health complication, encompassing excessive inflammatory response, oxidative stress, and tubular necrosis; leading to kidney failure and death. Sepsis treatments are nonspecific and palliative. In this study, we evaluated the effect of morin, a flavonoid with known nephroprotective capabilities, on sepsis-induced AKI by dividing eighty male mice into: normal, morin-treated, septic, and septic mice treated with morin. Half of the groups were sacrified 3 days post sepsis induction, while the rest was sacrified on the 7th day. Treating septic mice with morin resulted in the amelioration of sepsis-associated pathophysiological renal alterations and the increase of the survival and recovery rates compared with those of septic control group. These findings indicate that morin has a therapeutic effect against sepsis-associated AKI via its anti-inflammatory, antioxidant and regenerative effects. Thus, it could be used as potential pharmacological intervention for preventing renal complications of sepsis.

Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1β, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.

The adverse effects of sepsis-associated acute kidney injury (SA-AKI) highlight the need for new biomarkers. Signal Peptide-Complement C1r/C1s, Uegf, Bmp1-Epidermal Growth Factor-like Domain-Containing Protein 2 (SCUBE2), important for angiogenesis and endothelial integrity, has been linked to increased mortality in models of lipopolysaccharide-induced lung injury. This research aimed to assess the utility of plasma SCUBE2 levels as a prognostic indicator for SA-AKI in intensive care unit (ICU) patients.

Between September 2020 and December 2022, our study enrolled ICU patients diagnosed with stage 3 SA-AKI. We collected demographic information, illness severity indices, and laboratory data, including plasma SCUBE2 and sepsis-triggered cytokine levels. We employed receiver operating characteristic curves and DeLong tests to assess the predictive accuracy for survival, Kaplan-Meier curves to evaluate the relative risk of death, and multivariate logistic regression to identify independent mortality predictors.

Among the total of 200 participants, the survivors had significantly higher plasma SCUBE2 levels (115.9 ng/mL) compared to those who died (35.6 ng/mL). SCUBE2 levels showed a positive correlation with the anti-inflammatory cytokine IL-10 and a negative correlation with the APACHE II score, SOFA score, C-reactive protein, and monocyte chemoattractant protein-1. Multivariate analysis revealed that elevated SCUBE2 and IL-10 levels were independently protective against mortality, and associated with the most favorable 30-day survival outcomes.

In ICU patients with stage 3 SA-AKI, lower plasma levels of SCUBE2 were correlated with elevated pro-inflammatory factors, which impacted survival outcomes. This suggests that SCUBE2 could be a potential biomarker for predicting prognosis in patients with SA-AKI.

Sepsis pathophysiology is complex and identifying effective treatments for sepsis remains challenging. The study aims to identify effective drugs and targets for sepsis through transcriptomic analysis of sepsis patients, repositioning analysis of compounds, and validation by animal models.

GSE185263 obtained from the GEO database that includes gene expression profiles of 44 healthy controls and 348 sepsis patients categorized by severity. Bioinformatic algorithms revealed the molecular, function, and immune characteristics of the sepsis, and constructed sepsis-related protein-protein interaction networks. Subsequently, Random Walk with Restart analysis was applied to identify candidate drugs for sepsis, which were tested in animal models for survival, inflammation, coagulation, and multi-organ damage.

Our analysis found 1862 genes linked to sepsis development, enriched in functions like neutrophil extracellular trap formation (NETs) and complement/coagulation cascades. With disease progression, immune activation-associated cells were inhibited, while immune suppression-associated cells were activated. Next, the drug repositioning method identified candidate drugs, such as alpha-1 antitrypsin, that may play a therapeutic role by targeting neutrophil elastase (NE) to inhibit NETs. Animal experiments proved that alpha-1 antitrypsin treatment can improve the survival rate, reduce sepsis score, reduce the levels of inflammation markers in serum, and alleviate muti-organ morphological damage in mice with sepsis. The further results showed that α-1 antitrypsin can inhibit the NETs by suppressing the NE for the treatment of sepsis.

Alpha-1 antitrypsin acted on the NE to inhibit NETs thereby protecting mice from sepsis-induced inflammation and coagulation.

Acute kidney injury (AKI) is a common clinical syndrome worldwide, with no effective treatment strategy. Renal ischemia-reperfusion (IR) injury is one of the main AKI features, and the excessive reactive oxygen species (ROS) production during reperfusion causes severe oxidative damage to the kidney. Loureirin C (LC), an active ingredient in the traditional Chinese medicine Chinese dragon's blood, possesses excellent antioxidative properties, but its role in renal IR injury is not clear. In this study, we evaluated the protective effects of LC against renal IR injury in vivo and in vitro by establishing a mice renal IR injury model and a human proximal renal tubular epithelial cell (HK-2) hypoxia/reoxygenation (HR) model. We found that LC ameliorated renal function and tissue structure injury and inhibited renal oxidative stress and ferroptosis in vivo. In vitro, LC scavenged ROS and attenuated mitochondrial dysfunction in HK-2 cells, thereby inhibiting oxidative cellular injury. Furthermore, we found that LC effectively promoted nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and activated downstream target genes heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) to enhance cellular antioxidant function. Moreover, NRF2 knockdown and pharmacological inhibition of NRF2 partially eliminated the protective effect of LC. These results confirm that LC can effectively inhibit renal IR injury, and the mechanism may be associated with NRF2 activation by LC.

Endothelial glycocalyx (EG) degradation occurs in septic humans and EG products can be used as biomarkers of endothelial injury. Information about EG biomarkers and their association with disease severity is lacking in hospitalized foals.

Measure serum syndecan-1 (SDC-1), heparan sulfate (HS), angiopoietin-2 (ANG-2), aldosterone (ALD), and plasma atrial natriuretic peptide (ANP) concentrations and to determine their association with disease severity and death in hospitalized foals.

Ninety foals ≤3 days old.

Prospective, multicenter, longitudinal study. Foals were categorized into hospitalized (n = 74; 55 septic; 19 sick nonseptic) and 16 healthy foals. Serum ([SDC-1], [HS], [ANG-2], [ALD]) and plasma (ANP) were measured over 72 hours using immunoassays.

Serum ([SDC-1], [HS], [ANG-2], [ALD]) and plasma (ANP) were significantly higher in hospitalized and septic than healthy foals (P < .05). Serum (ANG-2) and plasma (ANP) were significantly higher in hospitalized nonsurvivors than in survivors (P < .05). On admission, hospitalized foals with serum (HS) > 58.7 ng/mL had higher odds of nonsurvival (odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.02-36.7). Plasma (ANP) >11.5 pg/mL was associated with the likelihood of nonsurvival in hospitalized foals (OR = 7.2; 95% CI = 1.4-37.4; P < .05). Septic foals with serum (ANG-2) >1018 pg/mL on admission had higher odds of nonsurvival (OR = 6.5; 95% CI =1.2-36.6; P < .05).

Critical illness in newborn foals is associated with EG degradation and injury, and these biomarkers are related to the severity of disease on admission and the outcome of sick foals.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid and significant decrease in renal function that can arise from various etiologies, and is associated with high morbidity and mortality. The renal tubular epithelial cells (TECs) represent the central cell type affected by AKI, and their notable regenerative capacity is critical for the recovery of renal function in afflicted patients. The adaptive repair process initiated by surviving TECs following mild AKI facilitates full renal recovery. Conversely, when injury is severe or persistent, it allows the TECs to undergo pathological responses, abnormal adaptive repair and phenotypic transformation, which will lead to the development of renal fibrosis. Given the implications of TECs fate after injury in renal outcomes, a deeper understanding of these mechanisms is necessary to identify promising therapeutic targets and biomarkers of the repair process in the human kidney.

Sepsis-induced acute kidney injury (S-AKI) is one of the most serious life-threatening complications of sepsis. The pathogenesis of S-AKI is complex and there is no effective specific treatment. Therefore, it is crucial to choose suitable preclinical models that are highly similar to human S-AKI to study the pathogenesis and drug treatment. In this review, we summarized recent advances in the development models of S-AKI, providing reference for the reasonable selection of experimental models as basic research and drug development of S-AKI.

Sepsis and septic shock are critical medical conditions characterized by a systemic inflammatory response to infection, significantly contributing to global mortality rates. The progression to multiple organ dysfunction syndrome (MODS) represents the most severe complication of sepsis and markedly increases clinical mortality. Central to the pathophysiology of sepsis, endothelial cells play a crucial role in regulating microcirculation and maintaining barrier integrity across various organs and tissues. Recent studies have underscored the pivotal role of endothelial function in the development of sepsis-induced MODS. This review aims to provide a comprehensive overview of the pathophysiology of sepsis-induced MODS, with a specific focus on endothelial dysfunction. It also compiles compelling evidence regarding potential small molecules that could attenuate sepsis and subsequent multi-organ damage by modulating endothelial function. Thus, this review serves as an essential resource for clinical practitioners involved in the diagnosing, managing, and providing intensive care for sepsis and associated multi-organ injuries, emphasizing the importance of targeting endothelial cells to enhance outcomes of the patients.

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Sepsis is now defined as a life-threatening syndrome of organ dysfunction triggered by a dysregulated host response to infection, posing significant challenges in critical care. The main objective of this review is to evaluate the potential of emerging biomarkers for early diagnosis and accurate prognosis in sepsis management, which are pivotal for enhancing patient outcomes. Despite advances in supportive care, traditional biomarkers like C-reactive protein and procalcitonin have limitations, and recent studies have identified novel biomarkers with increased sensitivity and specificity, including circular RNAs, HOXA distal transcript antisense RNA, microRNA-486-5p, protein C, triiodothyronine, and prokineticin 2. These emerging biomarkers hold promising potential for the early detection and prognostication of sepsis. They play a crucial role not only in diagnosis but also in guiding antibiotic therapy and evaluating treatment effectiveness. The introduction of point-of-care testing technologies has brought about a paradigm shift in biomarker application, enabling swift and real-time patient evaluation. Despite these advancements, challenges persist, notably concerning biomarker variability and the lack of standardized thresholds. This review summarizes the latest advancements in sepsis biomarker research, spotlighting the progress and clinical implications. It emphasizes the significance of multi-biomarker strategies and the feasibility of personalized medicine in sepsis management. Further verification of biomarkers on a large scale and their integration into clinical practice are advocated to maximize their efficacy in future sepsis treatment.

Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.

Renal fibrosis, a critical factor in the development of chronic kidney disease (CKD), is predominantly initiated by acute kidney injury (AKI) and subsequent maladaptive repair resulting from pharmacological or pathological stimuli. Phosphatase and tensin homolog (PTEN), also known as phosphatase and tensin-associated phosphatase, plays a pivotal role in regulating the physiological behavior of renal tubular epithelial cells, glomeruli, and renal interstitial cells, thereby preserving the homeostasis of renal structure and function. It significantly impacts cell proliferation, apoptosis, fibrosis, and mitochondrial energy metabolism during AKI-to-CKD transition. Despite gradual elucidation of PTEN's involvement in various kidney injuries, its specific role in AKI and maladaptive repair after injury remains unclear. This review endeavors to delineate the multifaceted role of PTEN in renal pathology during AKI and CKD progression along with its underlying mechanisms, emphasizing its influence on oxidative stress, autophagy, non-coding RNA-mediated recruitment and activation of immune cells as well as renal fibrosis. Furthermore, we summarize prospective therapeutic targeting strategies for AKI and CKD-treatment related diseases through modulation of PTEN.