HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury
RationaleAcute kidney injury (AKI) is a clinical syndrome associated with a multitude of conditions. Although renal replacement therapy (RRT) remains the cornerstone of treatment for advanced AKI, its implementation can potentially pose risks and may not be readily accessible across all healthcare s...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1475543/full |
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| author | Li Zhu Li Zhu Qiang Zheng Xiaodong Liu Xiaodong Liu Hao Ding Mengqing Ma Jiaxin Bao Yawen Cai Changchun Cao |
| author_facet | Li Zhu Li Zhu Qiang Zheng Xiaodong Liu Xiaodong Liu Hao Ding Mengqing Ma Jiaxin Bao Yawen Cai Changchun Cao |
| author_sort | Li Zhu |
| collection | DOAJ |
| description | RationaleAcute kidney injury (AKI) is a clinical syndrome associated with a multitude of conditions. Although renal replacement therapy (RRT) remains the cornerstone of treatment for advanced AKI, its implementation can potentially pose risks and may not be readily accessible across all healthcare settings and regions. Elevated lactate levels are implicated in sepsis-induced AKI; however, it remains unclear whether increased lactate directly induces AKI or elucidates the underlying mechanisms.MethodsFor human, the measurement of lactate in arterial blood gas is performed using the direct determination of L-lactate through an electrode oxidation method by a blood gas analyzer. For mice, enzyme-linked immunosorbent assay (ELISA) kits were employed to quantify the concentrations of lactate and AKI biomarkers in blood and cell supernatant. The mouse model of AKI was performed with a single intraperitoneal (i.p.) administration of lactate (30 mg/kg) and low-dose LPS (2 mg/kg) for 24 h. Proteomic analysis was conducted to identify lactylated proteins in kidney tissues. Techniques such as, immunoprecipitation, western blotting and immunofluorescence were used to evaluate the levels of HMGB1 lactylation, neutrophil extracellular traps (NETs)and to assess related molecular signaling pathways.Main resultsOur findings indicate that lactate serves as an independent predictor of AKI in patients with acute decompensated heart failure (ADHF). We observed that co-administration of lactate with low-dose lipopolysaccharide (LPS) resulted in lactate overproduction, which subsequently elevated serum levels of creatinine (Cre) and blood urea nitrogen (BUN). Furthermore, the combined application of lactate and low-dose LPS was shown to provoke HMGB1 lactylation within renal tissues. Notably, pretreatment with HMGB1 small interfering RNA (siRNA) effectively diminished lactate-mediated HMGB1 lactylation and alleviated the severity of AKI. Additionally, lactate accumulation was found to enhance the expression levels of NETs in the bloodstream, with circulating NETs levels positively correlating with HMGB1 lactylation. Importantly, pre-administration of HMGB1 inhibitors (glycyrrhizin) or lactate dehydrogenase A (LDH-A) inhibitors (oxamate) reversed the upregulation of NETs induced by lactate and low-dose LPS in both the blood and polymorphonuclear neutrophils (PMNs) cell supernatant, thereby ameliorating AKI associated with lactate accumulation.ConclusionsThese findings illuminate the role of lactate-mediated HMGB1 lactylation in inducing AKI in mice through the activation of the HMGB1-NETs signaling pathway. |
| format | Article |
| id | doaj-art-b4d1d17ab8824ecabeae4943b1fbfa45 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-b4d1d17ab8824ecabeae4943b1fbfa452025-01-09T05:10:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14755431475543HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injuryLi Zhu0Li Zhu1Qiang Zheng2Xiaodong Liu3Xiaodong Liu4Hao Ding5Mengqing Ma6Jiaxin Bao7Yawen Cai8Changchun Cao9Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of Nephrology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, ChinaDepartment of Nephrology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, ChinaDepartment of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, ChinaThe Second People’s Hospital of Lianyungang, Affiliated to Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, ChinaDepartment of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, ChinaDepartment of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, ChinaDepartment of Nephrology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, ChinaDepartment of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, ChinaRationaleAcute kidney injury (AKI) is a clinical syndrome associated with a multitude of conditions. Although renal replacement therapy (RRT) remains the cornerstone of treatment for advanced AKI, its implementation can potentially pose risks and may not be readily accessible across all healthcare settings and regions. Elevated lactate levels are implicated in sepsis-induced AKI; however, it remains unclear whether increased lactate directly induces AKI or elucidates the underlying mechanisms.MethodsFor human, the measurement of lactate in arterial blood gas is performed using the direct determination of L-lactate through an electrode oxidation method by a blood gas analyzer. For mice, enzyme-linked immunosorbent assay (ELISA) kits were employed to quantify the concentrations of lactate and AKI biomarkers in blood and cell supernatant. The mouse model of AKI was performed with a single intraperitoneal (i.p.) administration of lactate (30 mg/kg) and low-dose LPS (2 mg/kg) for 24 h. Proteomic analysis was conducted to identify lactylated proteins in kidney tissues. Techniques such as, immunoprecipitation, western blotting and immunofluorescence were used to evaluate the levels of HMGB1 lactylation, neutrophil extracellular traps (NETs)and to assess related molecular signaling pathways.Main resultsOur findings indicate that lactate serves as an independent predictor of AKI in patients with acute decompensated heart failure (ADHF). We observed that co-administration of lactate with low-dose lipopolysaccharide (LPS) resulted in lactate overproduction, which subsequently elevated serum levels of creatinine (Cre) and blood urea nitrogen (BUN). Furthermore, the combined application of lactate and low-dose LPS was shown to provoke HMGB1 lactylation within renal tissues. Notably, pretreatment with HMGB1 small interfering RNA (siRNA) effectively diminished lactate-mediated HMGB1 lactylation and alleviated the severity of AKI. Additionally, lactate accumulation was found to enhance the expression levels of NETs in the bloodstream, with circulating NETs levels positively correlating with HMGB1 lactylation. Importantly, pre-administration of HMGB1 inhibitors (glycyrrhizin) or lactate dehydrogenase A (LDH-A) inhibitors (oxamate) reversed the upregulation of NETs induced by lactate and low-dose LPS in both the blood and polymorphonuclear neutrophils (PMNs) cell supernatant, thereby ameliorating AKI associated with lactate accumulation.ConclusionsThese findings illuminate the role of lactate-mediated HMGB1 lactylation in inducing AKI in mice through the activation of the HMGB1-NETs signaling pathway.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1475543/fulllactateHMGB1 lactylationneutrophil extracellular traps (NETs)acute kidney injuryLPS |
| spellingShingle | Li Zhu Li Zhu Qiang Zheng Xiaodong Liu Xiaodong Liu Hao Ding Mengqing Ma Jiaxin Bao Yawen Cai Changchun Cao HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury Frontiers in Immunology lactate HMGB1 lactylation neutrophil extracellular traps (NETs) acute kidney injury LPS |
| title | HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury |
| title_full | HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury |
| title_fullStr | HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury |
| title_full_unstemmed | HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury |
| title_short | HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury |
| title_sort | hmgb1 lactylation drives neutrophil extracellular trap formation in lactate induced acute kidney injury |
| topic | lactate HMGB1 lactylation neutrophil extracellular traps (NETs) acute kidney injury LPS |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1475543/full |
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