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JASN:尿液代谢物帮助检测糖尿病肾病线粒体功能

来源:生物谷 2013-10-11 19:42

2013年10月12日讯 /生物谷BIOON/--近日,加州大学圣地亚哥医学院研究人员发现13个代谢物(细胞代谢所产生的小分子),在糖尿病并发慢性肾脏疾病患者中与健康对照组相比有显著不同。

13种代谢物中的12个与线粒体功能有关,这表明线粒体功能被抑制是糖尿病肾病的基本特征。该研究结果将发表在11月的Journal of the American Society of Nephrology杂志上。

第一作者Kumar Sharma医学博士说:这项工作提供了强有力的证据表明,线粒体功能降低是糖尿病肾病的主要特征。

研究发现,一个特定的细胞通路AMPK-PGC1a可能在线粒体功能和数量减少中起着关键的作用,这意味着恢复和增加线粒体功能和数量的新治疗方法可以减缓慢性肾脏病。

据估计,在美国有26万成年人患有慢性肾脏病(CKD),数以百万计人患病风险增加。这些患者往往需要透析或器官移植。慢性肾脏病的主要原因是高血压和糖尿病,在过去十年,CKD和糖尿病的发生率急剧上升,尤其是对于65岁及以上的人。

Sharma和他的同事们对193个(糖尿病并发慢性肾脏病患者、糖尿病但不患CKD的患者以及健康对照组)尿液样本进行分析后,量化样品中的94个代谢产物。发现13个代谢物在糖尿病并发慢性肾脏病患者中与对照组相比,存在显著差异。

糖尿病并发慢性肾脏病患者尿液样本中12个代谢产物,与糖尿病但没有并发CKD的患者相比也存在显著差异。这12个代谢物在线粒体代谢中发挥作用,并在糖尿病并发慢性肾脏病的患者处于较低水平,这表明糖尿病并发症至少部分是由线粒体活性被抑制引起的。

Sharma说,测量尿液中代谢产物用于检测和评估糖尿病肾病是一个重要的诊断步骤,尿液中的代谢物可以在生物化学和细胞水平上揭示肾脏的基本功能。(生物谷Bioon.com)

Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease

Kumar Sharma,et al.

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 (P≤0.001), 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 PGC1α (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.

 

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