Nuclear Magnetic Resonance Metabolomic Profiling of Mouse Kidney, Urine and Serum Following Renal Ischemia/Reperfusion Injury.
Nuclear Magnetic Resonance Metabolomic Profiling of Mouse Kidney, Urine and Serum Following Renal Ischemia/Reperfusion Injury.
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DOI：
10.1371/journal.pone.0163021
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
de Tullio P
中科院分区：
文献类型：
--
作者：
Jouret F;Leenders J;Poma L;Defraigne JO;Krzesinski JM;de Tullio P
缺血/再灌注（I/R）是急性肾损伤（AKI）的最常见原因。其病理生理学仍不清楚。代谢组学致力于识别参与综合生命系统（病理）生理变化的代谢物。在这里，我们使用来自肾 I/R 小鼠模型的尿液、血清和肾脏样本进行 1H 核磁共振代谢组学。通过双侧夹住血管蒂诱导 12 周龄 C57BL/6J 雄性小鼠肾缺血 30 分钟，然后进行 6、24 或 48 小时再灌注（n = 12/组）。使用假手术小鼠作为对照。在每个时间点对尿液、血清和肾脏裂解物进行统计判别分析，即主成分分析和潜在结构正交投影 (OPLS-DA)。绘制多变量受试者工作特征 (ROC) 曲线，并根据 ROC 混淆矩阵（100 次交叉验证的平均类别概率）计算灵敏度和特异性。尿液 OPLS-DA 分析显示 I/R 组和假手术组之间存在净分离，牛磺酸、二甲胺和三甲胺、肌酸和乳酸水平存在显着差异。早在再灌注后6小时就观察到了这种变化。主要代谢组改变发生在再灌注后 24 小时。此时，尿液光谱与常规 AKI 生物标志物（即血清肌酐和尿素水平）之间的相关系数分别达到 0.94 和 0.95。术后6小时、24小时和48小时的ROC曲线下面积分别为0.73、0.98和0.97。在肾脏样本中也发现了类似的差异，乳酸、脂肪酸、胆碱和牛磺酸的水平发生了变化。相比之下，血清 OPLS-DA 分析无法区分假手术动物和 I/R 暴露动物。我们的研究表明，小鼠肾缺血再灌注会导致尿液和肾脏成分发生早期和持续的代谢组变化。再灌注后 6 小时和 24 小时最相关的途径包括糖异生、牛磺酸和亚牛磺酸代谢，而蛋白质生物合成、糖酵解以及半乳糖和精氨酸代谢是再灌注后 48 小时的关键。
Ischemia/reperfusion (I/R) is the most common cause of acute kidney injury (AKI). Its pathophysiology remains unclear. Metabolomics is dedicated to identify metabolites involved in (patho)physiological changes of integrated living systems. Here, we performed 1H-Nuclear Magnetic Resonance metabolomics using urine, serum and kidney samples from a mouse model of renal I/R. Renal 30-min ischemia was induced in 12-week-old C57BL/6J male mice by bilaterally clamping vascular pedicles, and was followed by 6, 24 or 48-hour reperfusion (n = 12/group). Sham-operated mice were used as controls. Statistical discriminant analyses, i.e. principal component analysis and orthogonal projections to latent structures (OPLS-DA), were performed on urine, serum and kidney lysates at each time-point. Multivariate receiver operating characteristic (ROC) curves were drawn, and sensitivity and specificity were calculated from ROC confusion matrix (with averaged class probabilities across 100 cross-validations). Urine OPLS-DA analysis showed a net separation between I/R and sham groups, with significant variations in levels of taurine, di- and tri-methylamine, creatine and lactate. Such changes were observed as early as 6 hours post reperfusion. Major metabolome modifications occurred at 24h post reperfusion. At this time-point, correlation coefficients between urine spectra and conventional AKI biomarkers, i.e. serum creatinine and urea levels, reached 0.94 and 0.95, respectively. The area under ROC curve at 6h, 24h and 48h post surgery were 0.73, 0.98 and 0.97, respectively. Similar discriminations were found in kidney samples, with changes in levels of lactate, fatty acids, choline and taurine. By contrast, serum OPLS-DA analysis could not discriminate sham-operated from I/R-exposed animals. Our study demonstrates that renal I/R in mouse causes early and sustained metabolomic changes in urine and kidney composition. The most implicated pathways at 6h and 24h post reperfusion include gluconeogenesis, taurine and hypotaurine metabolism, whereas protein biosynthesis, glycolysis, and galactose and arginine metabolism are key at 48h post reperfusion.
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影响因子：
64.8
作者：
Sreekumar, Arun;Poisson, Laila M.;Rajendiran, Thekkelnaycke M.;Khan, Amjad P.;Cao, Qi;Yu, Jindan;Laxman, Bharathi;Mehra, Rohit;Lonigro, Robert J.;Li, Yong;Nyati, Mukesh K.;Ahsan, Aarif;Kalyana-Sundaram, Shanker;Han, Bo;Cao, Xuhong;Byun, Jaeman;Omenn, Gilbert S.;Ghosh, Debashis;Pennathur, Subramaniam;Alexander, Danny C.;Berger, Alvin;Shuster, Jeffrey R.;Wei, John T.;Varambally, Sooryanarayana;Beecher, Christopher;Chinnaiyan, Arul M.
通讯作者：
Chinnaiyan, Arul M.
影响因子：
6.1
作者：
Atzler, Dorothee;Schwedhelm, Edzard;Zeller, Tanja
通讯作者：
Zeller, Tanja
影响因子：
4
作者：
Kempson SA;Zhou Y;Danbolt NC
通讯作者：
Danbolt NC
影响因子：
6
作者：
Naito, Masayo;Bomsztyk, Karol;Zager, Richard A.
通讯作者：
Zager, Richard A.
影响因子：
2.8
作者：
Liu, Ye;Yan, Shikai;Mei, Changlin
通讯作者：
Mei, Changlin