NMR-based serum and urine metabolomic profile reveals suppression of mitochondrial pathways in experimental sepsis-associated acute kidney injury.
NMR-based serum and urine metabolomic profile reveals suppression of mitochondrial pathways in experimental sepsis-associated acute kidney injury.
复制标题
基于 NMR 的血清和尿液代谢组学谱揭示了实验性脓毒症相关急性肾损伤中线粒体途径的抑制。
DOI：
10.1152/ajprenal.00582.2020
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Kennedy,MichaelA
中科院分区：
文献类型：
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作者：
Standage,StephenW;Xu,Shenyuan;Brown,Lauren;Ma,Qing;Koterba,Adeleine;Lahni,Patrick;Devarajan,Prasad;Kennedy,MichaelA
脓毒症相关急性肾损伤（SA-AKI）是危重症患者中引起死亡增加的一个重要问题。对这种疾病的新认识涉及其病理生理学中的代谢功能障碍。本研究旨在确定适合潜在治疗干预的特定代谢途径。采用小鼠脓毒症模型，收集血液和组织样本，评估全身炎症、肾功能和肾损伤。基于核磁共振（NMR）的代谢组学量化了血清和尿液中的数十种代谢物，随后提交给通路分析。肾组织基因表达分析证实了相关途径。脓毒症小鼠炎症细胞因子循环水平升高，血尿素氮和肌酐水平升高，表明全身性炎症和肾功能不佳。脓毒症时肾组织仅表现出轻微的组织学损伤。核磁共振代谢组学分析确定了SA-AKI中与支链氨基酸代谢、脂肪酸氧化和新生NAD+生物合成相关的线粒体通路的参与。与这些途径相关的肾皮质酶基因表达明显受到抑制。高炎症的脓毒症小鼠的肾皮质脂肪酸氧化率较低，这与较高的血清肌酐水平相关。与人类相似，脓毒症小鼠表现出肾功能障碍，但没有明显的组织破坏，表明代谢紊乱是SA-AKI病理生理的重要因素。以线粒体功能为中心的支链氨基酸和脂肪酸的代谢以及NAD+的合成似乎受到抑制。开发干预措施来激活这些通路可能为SA-AKI提供新的治疗机会。基于ynmr的代谢组学揭示了脓毒症相关急性肾损伤中支链氨基酸代谢、脂肪酸氧化和NAD+合成的中断。这些途径代表了肾小管上皮细胞能量供应的基本过程，可能代表了治疗干预的靶向机制。
Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine that were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed the implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histological evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid metabolism, fatty acid oxidation, and de novo NAD+biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Renal cortical fatty acid oxidation rates were lower in septic mice with high inflammation, and this correlated with higher serum creatinine levels. Similar to humans, septic mice demonstrated renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of branched-chain amino acid and fatty acids and NAD+synthesis, which all center on mitochondrial function, appeared to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI.NEW & NOTEWORTHYNMR-based metabolomics revealed disruptions in branched-chain amino acid metabolism, fatty acid oxidation, and NAD+synthesis in sepsis-associated acute kidney injury. These pathways represent essential processes for energy provision in renal tubular epithelial cells and may represent targetable mechanisms for therapeutic intervention.