A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease
A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease
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DOI：
10.1152/ajprenal.00722.2009
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发表时间：
2010-04-01
影响因子：
4.2
通讯作者：
Weiss, Robert H.
中科院分区：
文献类型：
--
作者：
Taylor, Sandra L.;Ganti, Sheila;Weiss, Robert H.
泰勒 SL、甘蒂 S、布卡诺夫 NO、查普曼 A、费恩 O、奥西尔 M、金 K、韦斯 RH。使用幼年囊性小鼠的代谢组学方法来识别多囊肾病的尿液生物标志物和改变的途径。 Am J Physiol Renal Physiol 298：F909-F922，2010。首次发表于 2010 年 2 月 3 日； doi:10.1152/ajprenal.00722.2009.-常染色体显性多囊肾病 (ADPKD) 是最常见的遗传性肾脏疾病，影响千分之一的个体。超声最常用于诊断 ADPKD；这种方法仅在疾病晚期、出现肉眼可见的囊肿后才有用。越来越多的证据表明，无论基因突变如何，人类和小鼠 PKD 的囊肿发生都有共同的细胞和分子机制，并且在复杂的代谢组学分析中，使用小鼠模型比人类研究在原理证明方面具有明显的优势。因此，在这项研究中，我们利用气相色谱-飞行时间质谱法进行基于尿液代谢组学的研究，以证明仅通过尿液分析即可将囊性小鼠与其野生型小鼠区分开来。在生命第 26 天，在出现肾功能障碍的血清学证据之前，受影响的小鼠可通过尿液代谢组学分析来区分；这一发现持续 45 天到 64 天，此时体重差异会混淆结果。使用功能评分分析和 KEGG 通路数据库，我们确定了几种生物学相关的代谢通路，这些通路在这种疾病的早期就发生了改变，其中最具代表性的是嘌呤和半乳糖代谢通路。此外，我们还确定了几种特定的候选生物标志物，包括尿囊酸和腺苷，它们在年轻囊性小鼠的尿液中含量增加。这些标记物和途径成分一旦扩展到人类疾病，可能会被证明可用作诊断囊性肾病的非侵入性手段并提出新的治疗方法。因此，尿液代谢组学对于囊性肾病具有巨大的诊断潜力，值得进一步研究。
Taylor SL, Ganti S, Bukanov NO, Chapman A, Fiehn O, Osier M, Kim K, Weiss RH. A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease. Am J Physiol Renal Physiol 298: F909-F922, 2010. First published February 3, 2010; doi:10.1152/ajprenal.00722.2009.-Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study. Therefore, in this study we utilized a urinary metabolomics-based investigation using gas chromatography-time of flight mass spectrometry to demonstrate that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 days until 64 days, at which time body weight differences confound the results. Using functional score analysis and the KEGG pathway database, we identify several biologically relevant metabolic pathways which are altered very early in this disease, the most highly represented being the purine and galactose metabolism pathways. In addition, we identify several specific candidate biomarkers, including allantoic acid and adenosine, which are augmented in the urine of young cystic mice. These markers and pathway components, once extended to human disease, may prove useful as a noninvasive means of diagnosing cystic kidney diseases and to suggest novel therapeutic approaches. Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study.