Pub Date : 2025-06-19DOI: 10.1016/j.trsl.2025.06.001
Yinghui Wang , Qingqing Zhang , Shasha Lv , Xueling Wang , Qingzhen Liu , Xiangchun Liu , Yaping Zhang , Gang Liu
Diabetic kidney disease (DKD) is a main cause of end-stage renal disorder, yet its pathogenesis is still incompletely understood. Ferroptosis has been implicated in DKD progression; however, its regulatory mechanisms remain unclear. Phosphoglycerate dehydrogenase (PHGDH), a key enzyme in serine biosynthesis, has been minimally studied in DKD development. To elucidate the roles of PHGDH in ferroptosis and its underlying mechanism in podocytes and DKD, we conducted this study. Our findings demonstrate that PHGDH deficiency exacerbates podocyte injury, characterized by cytoskeletal disorganization, and promotes ferroptosis in both podocytes and DKD renal tissues. Conversely, PHGDH overexpression alleviates podocyte injury, reduces ferroptosis, and improves renal function in DKD mice. Mechanistically, we identified that PHGDH mediates ferroptosis by regulating SLC7A11 expression, a key ferroptosis-related protein. Specifically, PHGDH stabilizes Y-box binding protein 1 (YB1) by inhibiting its K48-linked ubiquitination and degradation, thereby enhancing SLC7A11 mRNA stability and expression. In conclusion, our study reveals a novel PHGDH-YB1-SLC7A11 regulatory axis that is responsible for suppressing ferroptosis and protecting against podocyte and renal injury in DKD. Our findings shed new light into the molecular mechanism underlying ferroptosis in DKD and highlight PHGDH as a therapeutic target for mitigating ferroptosis-mediated renal damage.
{"title":"PHGDH alleviates DKD by regulating YB1/SLC7A11-mediated ferroptosis in podocytes","authors":"Yinghui Wang , Qingqing Zhang , Shasha Lv , Xueling Wang , Qingzhen Liu , Xiangchun Liu , Yaping Zhang , Gang Liu","doi":"10.1016/j.trsl.2025.06.001","DOIUrl":"10.1016/j.trsl.2025.06.001","url":null,"abstract":"<div><div>Diabetic kidney disease (DKD) is a main cause of end-stage renal disorder, yet its pathogenesis is still incompletely understood. Ferroptosis has been implicated in DKD progression; however, its regulatory mechanisms remain unclear. Phosphoglycerate dehydrogenase (PHGDH), a key enzyme in serine biosynthesis, has been minimally studied in DKD development. To elucidate the roles of PHGDH in ferroptosis and its underlying mechanism in podocytes and DKD, we conducted this study. Our findings demonstrate that PHGDH deficiency exacerbates podocyte injury, characterized by cytoskeletal disorganization, and promotes ferroptosis in both podocytes and DKD renal tissues. Conversely, PHGDH overexpression alleviates podocyte injury, reduces ferroptosis, and improves renal function in DKD mice. Mechanistically, we identified that PHGDH mediates ferroptosis by regulating SLC7A11 expression, a key ferroptosis-related protein. Specifically, PHGDH stabilizes Y-box binding protein 1 (YB1) by inhibiting its K48-linked ubiquitination and degradation, thereby enhancing SLC7A11 mRNA stability and expression. In conclusion, our study reveals a novel PHGDH-YB1-SLC7A11 regulatory axis that is responsible for suppressing ferroptosis and protecting against podocyte and renal injury in DKD. Our findings shed new light into the molecular mechanism underlying ferroptosis in DKD and highlight PHGDH as a therapeutic target for mitigating ferroptosis-mediated renal damage.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"282 ","pages":"Pages 1-13"},"PeriodicalIF":6.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-29DOI: 10.1016/j.trsl.2025.05.007
Hua Zhang , Gang Shi , Yamei Li , Chao Wang , Yong Zhang , Yan Luo , Jia Xu , Yusha Qiu , Jinhu Ma , Jin Yang , Dandan Liao , Yihua Chen , Hongxin Deng
Colorectal cancer (CRC) is one of the most common cancers worldwide. Although immune checkpoint blockade (ICB) has transformed CRC treatment, the low response rate and immune resistance remain significant challenges. In recent years, epigenetic therapies have been shown to induce viral mimicry response to overcome immune resistance and increase the effectiveness of ICB. However, as an epigenetic modifier, the intrinsic function of PRMT5 in controlling innate immune signaling, viral mimicry, and the tumor microenvironment in CRC remains to be elucidated. Here, we report that PRMT5 inhibition attenuates CRC growth and epigenetically targeting PRMT5 remolds the tumor immune microenvironment, thereby enhancing the therapeutic efficacy of ICB. Mechanistically, PRMT5 knockdown increases endogenous retroviruses (ERVs) expression and dsRNA formation and causes DNA repair incompetence and genomic instability. These changes, combined with the elevated expression of RIG-I/MDA5/STING, trigger innate immune activation and viral mimicry response, thereby facilitating immune cell infiltration and enhancing ICB effectiveness. Furthermore, PRMT5 knockdown reduces H3R2me2s and H3R8me2s levels, and epigenetically promotes innate immune responses. Our study reveals the tumor intrinsic role of PRMT5 in controlling ERVs and innate sensors expression, providing perspectives for the epigenetically targeting of PRMT5 to induce viral mimicry response and enhance antitumor immunity in CRC.
{"title":"Epigenetically targeting PRMT5 promotes antitumor immunity by inducing endogenous retroviruses expression and triggering viral mimicry response","authors":"Hua Zhang , Gang Shi , Yamei Li , Chao Wang , Yong Zhang , Yan Luo , Jia Xu , Yusha Qiu , Jinhu Ma , Jin Yang , Dandan Liao , Yihua Chen , Hongxin Deng","doi":"10.1016/j.trsl.2025.05.007","DOIUrl":"10.1016/j.trsl.2025.05.007","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the most common cancers worldwide. Although immune checkpoint blockade (ICB) has transformed CRC treatment, the low response rate and immune resistance remain significant challenges. In recent years, epigenetic therapies have been shown to induce viral mimicry response to overcome immune resistance and increase the effectiveness of ICB. However, as an epigenetic modifier, the intrinsic function of PRMT5 in controlling innate immune signaling, viral mimicry, and the tumor microenvironment in CRC remains to be elucidated. Here, we report that PRMT5 inhibition attenuates CRC growth and epigenetically targeting PRMT5 remolds the tumor immune microenvironment, thereby enhancing the therapeutic efficacy of ICB. Mechanistically, PRMT5 knockdown increases endogenous retroviruses (ERVs) expression and dsRNA formation and causes DNA repair incompetence and genomic instability. These changes, combined with the elevated expression of RIG-I/MDA5/STING, trigger innate immune activation and viral mimicry response, thereby facilitating immune cell infiltration and enhancing ICB effectiveness. Furthermore, PRMT5 knockdown reduces H3R2me2s and H3R8me2s levels, and epigenetically promotes innate immune responses. Our study reveals the tumor intrinsic role of PRMT5 in controlling ERVs and innate sensors expression, providing perspectives for the epigenetically targeting of PRMT5 to induce viral mimicry response and enhance antitumor immunity in CRC.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 55-68"},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-29DOI: 10.1016/j.trsl.2025.05.009
Petra Košútová , Nikollet Nemcová , Maroš Kolomazník , Andrea Čalkovská , Pavol Mikolka
Background
Acute respiratory distress syndrome (ARDS) is characterised by severe inflammation and pulmonary edema, often leading to respiratory failure. This study aims to develop a stable and relevant rabbit model of severe ARDS using hydrochloric acid (HCl) aspiration and ventilator-induced lung injury (VILI).
Methods
Adult New Zealand rabbits were divided into four groups: Saline (n = 9), 1-hit 3.0 (HCl 3 ml/kg, n = 7), 1-hit 6.0 (HCl 6 ml/kg, n = 7), and 2-hit (HCl 3 ml/kg and ventilation with VT 20 ml/kg, zero PEEP, RR 20-30 bpm, and FiO2 1.0 to mimic VILI, n = 14). PaO2/FiO2 ratio, oxygenation index, oxygen saturation, PaCO2, ventilation efficiency index and alveolar-arterial gradient were evaluated every hour for 4 h after induction of lung injury. The post-mortem analysis included total and differential cell counts in bronchoalveolar lavage fluid (BALF), evaluation of lung edema formation, biochemical and histological examination of lung tissue.
Results
In the 2-hit group, we observed a significant deterioration of all lung function parameters (P/F ratio, oxygenation index, ventilation efficiency index, and alveolar-arterial gradient) compared to the saline group. Similarly, a deterioration was observed in the 1-hit 6.0 group. When analysing the inflammatory profile, we observed significantly increased levels of chemokines and cytokines (TNFα, IL-1β, IL-6, IL-8, ET-1, MCP, H1F, MIP) and oxidative stress parameters (3NT, MDA, AOPP, catalase and GSH/GSSG) in BALF in the 2-hit group compared to the saline group. Intratracheal administration of HCl alone did not have a significant impact on inflammation as the combination of two insults. An increased wet-to-dry lung weight ratio (W/D), indicative of pulmonary edema, was observed in both the 2-hit and 1-hit 6.0 groups compared to the saline group. An increased level of protein content in BALF and total lung injury score were observed in the 2-hit group compared to the saline group, 1-hit 3.0 and 1-hit 6.0.
Conclusion
The combination of hydrochloric acid aspiration and ventilator-induced lung injury reliably reproduces key features of severe ARDS, offering a robust and clinically relevant model for investigating its complex pathophysiology and evaluating novel therapeutic interventions.
{"title":"A novel rabbit model of severe ARDS: Synergistic effects of acid aspiration and harmful mechanical ventilation","authors":"Petra Košútová , Nikollet Nemcová , Maroš Kolomazník , Andrea Čalkovská , Pavol Mikolka","doi":"10.1016/j.trsl.2025.05.009","DOIUrl":"10.1016/j.trsl.2025.05.009","url":null,"abstract":"<div><h3>Background</h3><div>Acute respiratory distress syndrome (ARDS) is characterised by severe inflammation and pulmonary edema, often leading to respiratory failure. This study aims to develop a stable and relevant rabbit model of severe ARDS using hydrochloric acid (HCl) aspiration and ventilator-induced lung injury (VILI).</div></div><div><h3>Methods</h3><div>Adult New Zealand rabbits were divided into four groups: Saline (<em>n</em> = 9), 1-hit 3.0 (HCl 3 ml/kg, <em>n</em> = 7), 1-hit 6.0 (HCl 6 ml/kg, <em>n</em> = 7), and 2-hit (HCl 3 ml/kg and ventilation with V<sub>T</sub> 20 ml/kg, zero PEEP, RR 20-30 bpm, and FiO<sub>2</sub> 1.0 to mimic VILI, <em>n</em> = 14). PaO<sub>2</sub>/FiO<sub>2</sub> ratio, oxygenation index, oxygen saturation, PaCO<sub>2</sub>, ventilation efficiency index and alveolar-arterial gradient were evaluated every hour for 4 h after induction of lung injury. The <em>post-mortem</em> analysis included total and differential cell counts in bronchoalveolar lavage fluid (BALF), evaluation of lung edema formation, biochemical and histological examination of lung tissue<em>.</em></div></div><div><h3>Results</h3><div>In the 2-hit group, we observed a significant deterioration of all lung function parameters (P/F ratio, oxygenation index, ventilation efficiency index, and alveolar-arterial gradient) compared to the saline group. Similarly, a deterioration was observed in the 1-hit 6.0 group. When analysing the inflammatory profile, we observed significantly increased levels of chemokines and cytokines (TNFα, IL-1β, IL-6, IL-8, ET-1, MCP, H1F, MIP) and oxidative stress parameters (3NT, MDA, AOPP, catalase and GSH/GSSG) in BALF in the 2-hit group compared to the saline group. Intratracheal administration of HCl alone did not have a significant impact on inflammation as the combination of two insults. An increased wet-to-dry lung weight ratio (W/D), indicative of pulmonary edema, was observed in both the 2-hit and 1-hit 6.0 groups compared to the saline group. An increased level of protein content in BALF and total lung injury score were observed in the 2-hit group compared to the saline group, 1-hit 3.0 and 1-hit 6.0.</div></div><div><h3>Conclusion</h3><div>The combination of hydrochloric acid aspiration and ventilator-induced lung injury reliably reproduces key features of severe ARDS, offering a robust and clinically relevant model for investigating its complex pathophysiology and evaluating novel therapeutic interventions.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 43-54"},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-24DOI: 10.1016/j.trsl.2025.05.005
Ruslan Rafikov , Debrah M. Thompson , Olga Rafikova , Sara M. Camp , Roberto A. Ribas , Ramon C. Sun , Matthew S. Gentry , Nancy G. Casanova , Joe G N Garcia
Acute Respiratory Distress Syndrome (ARDS), characterized by the rapid onset of respiratory failure and mortality rates of ∼40%, remains a significant challenge in critical care medicine. Despite advances in supportive care, accurate prediction of ARDS mortality remains challenging, resulting in delayed delivery of targeted interventions and effective disease management. Traditional critical illness severity scores lack specificity for ARDS, underscoring the need for more precise prognostic tools for ARDS mortality. To address this crucial gap, we employed a multimodal approach to predict ARDS patients utilizing a comprehensive dataset comprised of integrated clinical, metabolomic, and biochemical/cytokine data from ARDS patients (collected within hours of ICU admission) to develop and validate predictive models of ARDS mortality risk. The most robust multimodal data model generated demonstrated superior predictive capability with an area under the curve (AUC) of 0.868 on the test set and 0.959 on the validation set. Notably, this model achieved perfect specificity in identifying non-survivors in the validation cohort, highlighting potential utility in guiding early and targeted interventions in ICU settings. Metabolomic analysis revealed significant alterations in crucial pathways associated with ARDS mortality with tryptophan metabolism, particularly the kynurenine pathway, emerging as the most significantly enriched metabolic route, as well as the NAD+ metabolism/nicotinamide phosphoribosyltransferase (NAMPT) and glycosaminoglycan biosynthesis pathways. These metabolic derangements were strongly confirmed by lipidomic/metabolomic analysis of lung tissues from a porcine sepsis/ARDS model. Together, these findings demonstrate the promise of integrating multimodal data to improve ARDS prognostication and to provide important insights into the complex metabolic derangements underlying severe ARDS. Identification of metabolic signatures, such as kynurenine and NAD+ metabolism/NAMPT pathways, may serve as a foundation for developing personalized and effective targeted interventions and management strategies for ARDS patients.
{"title":"Predictive modeling of ARDS mortality integrating biomarker/cytokine, clinical and metabolomic data","authors":"Ruslan Rafikov , Debrah M. Thompson , Olga Rafikova , Sara M. Camp , Roberto A. Ribas , Ramon C. Sun , Matthew S. Gentry , Nancy G. Casanova , Joe G N Garcia","doi":"10.1016/j.trsl.2025.05.005","DOIUrl":"10.1016/j.trsl.2025.05.005","url":null,"abstract":"<div><div>Acute Respiratory Distress Syndrome (ARDS), characterized by the rapid onset of respiratory failure and mortality rates of ∼40%, remains a significant challenge in critical care medicine. Despite advances in supportive care, accurate prediction of ARDS mortality remains challenging, resulting in delayed delivery of targeted interventions and effective disease management. Traditional critical illness severity scores lack specificity for ARDS, underscoring the need for more precise prognostic tools for ARDS mortality. To address this crucial gap, we employed a multimodal approach to predict ARDS patients utilizing a comprehensive dataset comprised of integrated clinical, metabolomic, and biochemical/cytokine data from ARDS patients (collected within hours of ICU admission) to develop and validate predictive models of ARDS mortality risk. The most robust multimodal data model generated demonstrated superior predictive capability with an area under the curve (AUC) of 0.868 on the test set and 0.959 on the validation set. Notably, this model achieved perfect specificity in identifying non-survivors in the validation cohort, highlighting potential utility in guiding early and targeted interventions in ICU settings. Metabolomic analysis revealed significant alterations in crucial pathways associated with ARDS mortality with tryptophan metabolism, particularly the kynurenine pathway, emerging as the most significantly enriched metabolic route, as well as the NAD+ metabolism/nicotinamide phosphoribosyltransferase (NAMPT) and glycosaminoglycan biosynthesis pathways. These metabolic derangements were strongly confirmed by lipidomic/metabolomic analysis of lung tissues from a porcine sepsis/ARDS model. Together, these findings demonstrate the promise of integrating multimodal data to improve ARDS prognostication and to provide important insights into the complex metabolic derangements underlying severe ARDS. Identification of metabolic signatures, such as kynurenine and NAD+ metabolism/NAMPT pathways, may serve as a foundation for developing personalized and effective targeted interventions and management strategies for ARDS patients.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 31-42"},"PeriodicalIF":6.4,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-22DOI: 10.1016/j.trsl.2025.05.004
Yue Yu , Han Chen , Rui Wang , Fei Xu, Jiasheng Yin, Tongtong Zang, Changyi Zhou, Chengpeng Liu, Chaofu Li, Li Shen, Junbo Ge
Secreted frizzled related protein 5 (sFRP5), an anti-inflammatory adipokine, plays a crucial role in various diseases, and its serum levels are low in patients with coronary artery disease (CAD). However, its role in atherosclerosis remains unclear. Therefore, we investigated the correlation between sFRP5 and plaque stability, along with the molecular mechanisms underlying atherosclerosis. In patients with CAD, serum sFRP5 levels were positively correlated with plaque stability, a predictor of thin-cap fibroatheromas (TCFAs). Recombinant sFRP5 (r-sFRP5) supplementation significantly increased plaque stability and ameliorated atherosclerosis progression in ApoE-/- mice. Aortic RNA-sequencing (RNA-seq) revealed sFRP5-mediated regulation in inflammatory cells. Our experiments confirmed that sFRP5 inhibits inflammation and macrophage migration. Mechanistically, Toll-like receptor 9 (TLR9) was identified as a downstream target of sFRP5, and sFRP5 suppressed TLR9 expression by decreasing c-Jun N-terminal kinase (JNK) phosphorylation. These findings suggest that serum sFRP5 levels are associated with plaque stability and play a protective role in atherosclerosis by attenuating inflammation and macrophage infiltration via inhibition of the JNK/TLR9 pathway, thereby ameliorating the progression of atherosclerosis. This study highlights the potential of sFRP5 as both a biomarker and therapeutic target for plaque stability in atherosclerosis.
分泌性卷曲相关蛋白5 （sFRP5）是一种抗炎脂肪因子，在多种疾病中起着至关重要的作用，其在冠状动脉疾病（CAD）患者的血清水平较低。然而，其在动脉粥样硬化中的作用尚不清楚。因此，我们研究了sFRP5与斑块稳定性之间的关系，以及动脉粥样硬化的分子机制。在冠心病患者中，血清sFRP5水平与斑块稳定性呈正相关，斑块稳定性是薄帽纤维粥样硬化（TCFAs）的预测因子。重组sFRP5 （r-sFRP5）补充显著增加ApoE-/-小鼠斑块稳定性和改善动脉粥样硬化进展。主动脉rna测序（RNA-seq）显示sfrp5介导的炎症细胞调节。我们的实验证实了sFRP5抑制炎症和巨噬细胞迁移。在机制上，toll样受体9 （TLR9）被确定为sFRP5的下游靶点，sFRP5通过降低c-Jun n -末端激酶（JNK）磷酸化来抑制TLR9的表达。这些研究结果表明，血清sFRP5水平与斑块稳定性有关，并通过抑制JNK/TLR9通路减轻炎症和巨噬细胞浸润，从而改善动脉粥样硬化的进展，从而在动脉粥样硬化中发挥保护作用。这项研究强调了sFRP5作为动脉粥样硬化斑块稳定性的生物标志物和治疗靶点的潜力。
{"title":"sFRP5 ameliorates atherosclerosis by suppressing the JNK/TLR9 pathway in macrophages","authors":"Yue Yu , Han Chen , Rui Wang , Fei Xu, Jiasheng Yin, Tongtong Zang, Changyi Zhou, Chengpeng Liu, Chaofu Li, Li Shen, Junbo Ge","doi":"10.1016/j.trsl.2025.05.004","DOIUrl":"10.1016/j.trsl.2025.05.004","url":null,"abstract":"<div><div>Secreted frizzled related protein 5 (sFRP5), an anti-inflammatory adipokine, plays a crucial role in various diseases, and its serum levels are low in patients with coronary artery disease (CAD). However, its role in atherosclerosis remains unclear. Therefore, we investigated the correlation between sFRP5 and plaque stability, along with the molecular mechanisms underlying atherosclerosis. In patients with CAD, serum sFRP5 levels were positively correlated with plaque stability, a predictor of thin-cap fibroatheromas (TCFAs). Recombinant sFRP5 (r-sFRP5) supplementation significantly increased plaque stability and ameliorated atherosclerosis progression in <em>ApoE<sup>-/-</sup></em> mice. Aortic RNA-sequencing (RNA-seq) revealed sFRP5-mediated regulation in inflammatory cells. Our experiments confirmed that sFRP5 inhibits inflammation and macrophage migration. Mechanistically, Toll-like receptor 9 (TLR9) was identified as a downstream target of sFRP5, and sFRP5 suppressed TLR9 expression by decreasing c-Jun N-terminal kinase (JNK) phosphorylation. These findings suggest that serum sFRP5 levels are associated with plaque stability and play a protective role in atherosclerosis by attenuating inflammation and macrophage infiltration via inhibition of the JNK/TLR9 pathway, thereby ameliorating the progression of atherosclerosis. This study highlights the potential of sFRP5 as both a biomarker and therapeutic target for plaque stability in atherosclerosis.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 1-13"},"PeriodicalIF":6.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-20DOI: 10.1016/j.trsl.2025.05.002
Zhixiang Bian, Xiangxiang Wang, Xiaoxuan Su, Ming Yang, Rui Zhu, Shunjie Chen
Objective
This study explored the molecular mechanism of adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) improving post-sepsis-associated acute kidney injury (S-AKI) tubular epithelial cell (TEC) apoptosis by modulating ADAM17/MerTK-mediated macrophage efferocytosis.
Methods
The S-AKI mouse model was established by caecal ligation and puncture and intravenously injected with ADSC-EVs. Mouse kidney macrophages were cultured with LPS, cultured with EVs while transfecting with oe-ADAM17 or si-MerTK, then incubated with Jurkat cells. Mouse serum urea and creatinine, and KIM-1, efferocytosis- and apoptosis-related protein, inflammatory factor, cytokine, and soluble MerTK (sMerTK) levels were determined using colorimetric assay, immunohistochemistry, Western blot, and ELISA. Renal tubular injury, TEC apoptosis, macrophage efferocytosis, and M1/M2 polarization levels were assessed via HE staining, TUNEL staining, immunofluorescence, and flow cytometry, respectively. In vivo validation experiments were conducted.
Results
S-AKI mice displayed elevated levels of serum urea, creatinine, KIM-1, pro-inflammatory factors, pro-apoptotic proteins and ADAM17 protein, decreased anti-apoptotic protein and MerTK protein levels, and diminished M2 polarization. ADSC-EVs down-regulated ADAM17 and sMerTK, and increased cell membrane MerTK, macrophage recognition of apoptotic cells and efferocytosis, and M2 polarization in renal tissues of S-AKI mice and LPS-induced mouse renal macrophages, indicating that ADSC-EVs regulated ADAM17/MerTK-mediated macrophage efferocytosis and promoted M2 polarization. MerTK silencing partially reversed ADSC-EVs-regulated LPS-induced mouse renal macrophage efferocytosis and M2 polarization. In vivo, ADAM17 upregulation partly averted ADSC-EVs-regulated post-S-AKI TEC apoptosis in mouse renal tissues.
Conclusion
ADSC-EVs down-regulated sMerTK level and up-regulated macrophage membrane MerTK protein level by modulating ADAM17 to promote macrophage efferocytosis and ameliorate post-S-AKI TEC apoptosis and inflammation.
{"title":"Mechanism of adipose-derived stem cell-derived extracellular vesicles affecting macrophage efferocytosis by mediating ADAM17/MerTK in the apoptosis of tubular epithelial cells after sepsis-associated acute kidney injury","authors":"Zhixiang Bian, Xiangxiang Wang, Xiaoxuan Su, Ming Yang, Rui Zhu, Shunjie Chen","doi":"10.1016/j.trsl.2025.05.002","DOIUrl":"10.1016/j.trsl.2025.05.002","url":null,"abstract":"<div><h3>Objective</h3><div>This study explored the molecular mechanism of adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) improving post-sepsis-associated acute kidney injury (S-AKI) tubular epithelial cell (TEC) apoptosis by modulating ADAM17/MerTK-mediated macrophage efferocytosis.</div></div><div><h3>Methods</h3><div>The S-AKI mouse model was established by caecal ligation and puncture and intravenously injected with ADSC-EVs. Mouse kidney macrophages were cultured with LPS, cultured with EVs while transfecting with oe-ADAM17 or si-MerTK, then incubated with Jurkat cells. Mouse serum urea and creatinine, and KIM-1, efferocytosis- and apoptosis-related protein, inflammatory factor, cytokine, and soluble MerTK (sMerTK) levels were determined using colorimetric assay, immunohistochemistry, Western blot, and ELISA. Renal tubular injury, TEC apoptosis, macrophage efferocytosis, and M1/M2 polarization levels were assessed via HE staining, TUNEL staining, immunofluorescence, and flow cytometry, respectively. <em>In vivo</em> validation experiments were conducted.</div></div><div><h3>Results</h3><div>S-AKI mice displayed elevated levels of serum urea, creatinine, KIM-1, pro-inflammatory factors, pro-apoptotic proteins and ADAM17 protein, decreased anti-apoptotic protein and MerTK protein levels, and diminished M2 polarization. ADSC-EVs down-regulated ADAM17 and sMerTK, and increased cell membrane MerTK, macrophage recognition of apoptotic cells and efferocytosis, and M2 polarization in renal tissues of S-AKI mice and LPS-induced mouse renal macrophages, indicating that ADSC-EVs regulated ADAM17/MerTK-mediated macrophage efferocytosis and promoted M2 polarization. MerTK silencing partially reversed ADSC-EVs-regulated LPS-induced mouse renal macrophage efferocytosis and M2 polarization. <em>In vivo</em>, ADAM17 upregulation partly averted ADSC-EVs-regulated post-S-AKI TEC apoptosis in mouse renal tissues.</div></div><div><h3>Conclusion</h3><div>ADSC-EVs down-regulated sMerTK level and up-regulated macrophage membrane MerTK protein level by modulating ADAM17 to promote macrophage efferocytosis and ameliorate post-S-AKI TEC apoptosis and inflammation.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 14-30"},"PeriodicalIF":6.4,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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