Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease
Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease
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DOI：
10.1681/asn.2013020126
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发表时间：
2013-11-01
影响因子：
13.6
通讯作者：
Naviaux, Robert K.
中科院分区：
文献类型：
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作者：
Sharma, Kumar;Karl, Bethany;Naviaux, Robert K.
糖尿病肾病是 ESRD 的主要原因，但糖尿病肾病的生物标志物很少。本研究使用气相色谱-质谱法对糖尿病 (DM) 和 CKD (DM+CKD) 患者、无 CKD 的 DM 患者 (DM-CKD) 以及健康对照的筛选和验证队列中的 94 种尿液代谢物进行定量。与健康对照组的水平相比，DM+CKD 队列中的 13 种代谢物显着降低（P0.001），并且与 DM-CKD 队列相比，13 种代谢物中的 12 种仍然显着。许多差异表达的代谢物是水溶性有机阴离子。值得注意的是，有机阴离子转运蛋白-1 (OAT1) 敲除小鼠表达了类似的尿液有机酸水平降低的模式，糖尿病肾病患者的人肾组织也表现出较低的 OAT1 和 OAT3 基因表达。生物信息学数据分析表明，13 种差异表达代谢物中的 12 种与线粒体代谢有关，并表明糖尿病肾病中线粒体活性受到整体抑制。支持这一分析的是，人类糖尿病肾切片表达较少的线粒体蛋白，来自糖尿病和 CKD 患者的尿液外泌体具有较少的线粒体 DNA，来自糖尿病肾病患者的肾组织具有较低的 PGC1（线粒体生物发生的主要调节因子）基因表达。我们的结论是，尿液代谢组学是糖尿病并发症生物标志物的可靠来源，我们的数据表明，糖尿病肾病中肾脏有机离子转运和线粒体功能失调。
Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM-CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P0.001), and 12 of the 13 remained significant when compared with the DM-CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1 (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.