Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients.
Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients.
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DOI：
10.1016/j.ebiom.2017.10.027
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发表时间：
2017-12
期刊：
影响因子：
11.1
通讯作者：
de Boer IH
中科院分区：
文献类型：
--
作者：
Hallan S;Afkarian M;Zelnick LR;Kestenbaum B;Sharma S;Saito R;Darshi M;Barding G;Raftery D;Ju W;Kretzler M;Sharma K;de Boer IH
慢性肾脏病（CKD）是一种流行率和死亡率极高的公共卫生问题。然而，缺乏有效的治疗选择，部分原因是对潜在的病理生理学知识不足。我们将代谢组学（GCMS）与肾脏基因表达研究相结合，以确定非糖尿病3-4期CKD成人与健康成人相比代谢途径的改变。27种代谢物的尿排泄率和33种代谢物的血浆浓度在CKD患者与对照组之间存在显著差异（估计范围为-68%至+113%）。途径分析显示，柠檬酸循环受到的影响最为显著，柠檬酸、顺乌头酸、异柠檬酸、2-酮戊二酸和琥珀酸的尿排泄减少40- 68%。在一个独立队列中重复了尿液中柠檬酸循环代谢物的减少。在肾活检中，乌头酸、异柠檬酸、2-酮戊二酸和琥珀酸调节基因的表达显著降低。我们在一项随机试验中观察到CKD患者在维生素D受体激动剂治疗期间尿柠檬酸盐排泄（+74%，p = 0.00009）和血浆2-酮戊二酸浓度（+12%，p = 0.002）增加。总之，在非糖尿病CKD中，柠檬酸循环代谢物的尿排泄和调节这些代谢物的基因的肾脏表达减少。这支持CKD作为线粒体功能障碍状态的新兴观点。60种代谢物的尿排泄率和血浆浓度在CKD患者与对照组之间存在显著差异。途径分析表明，柠檬酸循环是最显着的影响。肾活检组织中调节TCA循环的基因表达显著降低。慢性肾脏病（CKD）非常常见，并发症和死亡的风险很高。晚期疾病患者有严重的疲劳，肾脏以外的器官功能障碍，糖，蛋白质和脂肪代谢紊乱。我们发现许多代谢物在肾脏患者与健康对照组中存在显著差异。分析显示，柠檬酸循环是受影响最显著的代谢途径。柠檬酸循环在细胞线粒体中进行，是燃料分子转化为能量的中心代谢枢纽。这支持了CKD是线粒体功能障碍状态的观点。
Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range − 68% to + 113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+ 74%, p = 0.00009) and plasma 2-oxoglutarate concentrations (+ 12%, p = 0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction. Urinary excretion rate and plasma concentration of 60 metabolites differed significantly in CKD patients versus controls. Pathway analysis revealed that the citric acid cycle was the most significantly affected. Expression of genes regulating TCA cycle was significantly reduced in kidney biopsies. Chronic kidney disease (CKD) is very common and carries a high risk of complications and death. Patients with advanced disease have severe fatigue, organ dysfunction beyond the kidneys, and disturbances in sugar, protein and fat metabolism. We found many metabolites that differed significantly in kidney patients versus healthy controls. Analysis revealed that the citric acid cycle was the most significantly affected metabolic pathway. The citric acid cycle is performed in the cells` mitochondria and is the central metabolic hub where fuel molecules are converted into energy. This supports the view of CKD as a state of mitochondrial dysfunction.
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影响因子：
13.6
作者：
Aronov, Pavel A.;Luo, Frank J. -G.;Meyer, Timothy W.
通讯作者：
Meyer, Timothy W.
影响因子：
19.6
作者：
通讯作者：
--
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
5.8
作者：
通讯作者：
--
影响因子：
13.6
作者：
de Boer, Ian H.;Zelnick, Leila;Utzschneider, Kristina
通讯作者：
Utzschneider, Kristina