通过代谢组学分析确定常染色体显性多囊肾病的早期尿液生物标志物和代谢途径改变。

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 Epub Date: 2023-05-04 DOI:10.1152/ajprenal.00301.2022
Eden A Houske, Matthew G Glimm, Annika R Bergstrom, Sally K Slipher, Hope D Welhaven, Mark C Greenwood, Greta M Linse, Ronald K June, Alan S L Yu, Darren P Wallace, Alyssa K Hahn
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引用次数: 0

摘要

常染色体显性多囊肾病(ADPKD)的特点是形成大量充满液体的囊肿,导致功能性肾小球逐渐丧失。目前,对该病早期诊断和预后指标的需求尚未得到满足。研究人员从早期 ADPKD 患者(48 人)和年龄、性别匹配的正常对照组(47 人)的尿液中提取代谢物,并采用液相色谱-质谱法进行分析。利用正交偏最小二乘法判别分析生成了早期 ADPKD 的全局代谢组图谱,以确定代谢途径的改变和可作为诊断和预后生物标志物候选的判别代谢物。全球代谢组图谱显示了类固醇激素生物合成和代谢、脂肪酸代谢、丙酮酸代谢、氨基酸代谢和尿素循环的改变。46 种代谢物特征被确定为候选诊断生物标记物。可用于早期检测的候选诊断生物标志物的显著特征包括肌酐、cAMP、脱氧胞苷单磷酸、各种雄激素(睾酮;5-α-雄甾烷-3,17,二酮;反式-脱氢雄甾酮)、甜菜碱醛、磷酸、胆碱、18-羟皮质酮和皮质醇。与疾病进展速度不同有关的代谢途径包括类固醇激素的生物合成和代谢、维生素 D3 代谢、脂肪酸代谢、磷酸戊糖途径、三羧酸循环、氨基酸代谢、硅酸代谢以及硫酸软骨素和硫酸肝素降解。41种代谢物特征被确定为候选预后生物标志物。值得注意的候选预后生物标志物包括乙醇胺、C20:4 氨基酰胺磷酸酯、孕酮、各种雄激素(5-α-二氢睾酮、雄甾酮、乙酰胆碱酮和表雄酮)、甜菜碱醛、炎症脂质(二十碳五烯酸、亚油酸和硬脂酸)和胆碱。我们的探索性数据支持早期 ADPKD 的代谢重编程,并证明了基于液相色谱-质谱联用技术的全球代谢组学分析能够检测代谢途径的改变,并将其作为新的治疗靶点和生物标记物,用于早期诊断和跟踪 ADPKD 的疾病进展。探索性数据集揭示了可能导致早期囊肿形成和疾病快速进展的代谢通路改变,这些改变可能是候选生物标记物的潜在治疗靶点和通路来源。根据这些结果,我们生成了一组早期 ADPKD 的候选诊断和预后生物标志物,供将来验证。
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Metabolomic profiling to identify early urinary biomarkers and metabolic pathway alterations in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous fluid-filled cysts that lead to progressive loss of functional nephrons. Currently, there is an unmet need for diagnostic and prognostic indicators of early stages of the disease. Metabolites were extracted from the urine of patients with early-stage ADPKD (n = 48 study participants) and age- and sex-matched normal controls (n = 47) and analyzed by liquid chromatography-mass spectrometry. Orthogonal partial least squares-discriminant analysis was used to generate a global metabolomic profile of early ADPKD for the identification of metabolic pathway alterations and discriminatory metabolites as candidates of diagnostic and prognostic biomarkers. The global metabolomic profile exhibited alterations in steroid hormone biosynthesis and metabolism, fatty acid metabolism, pyruvate metabolism, amino acid metabolism, and the urea cycle. A panel of 46 metabolite features was identified as candidate diagnostic biomarkers. Notable putative identities of candidate diagnostic biomarkers for early detection include creatinine, cAMP, deoxycytidine monophosphate, various androgens (testosterone; 5-α-androstane-3,17,dione; trans-dehydroandrosterone), betaine aldehyde, phosphoric acid, choline, 18-hydroxycorticosterone, and cortisol. Metabolic pathways associated with variable rates of disease progression included steroid hormone biosynthesis and metabolism, vitamin D3 metabolism, fatty acid metabolism, the pentose phosphate pathway, tricarboxylic acid cycle, amino acid metabolism, sialic acid metabolism, and chondroitin sulfate and heparin sulfate degradation. A panel of 41 metabolite features was identified as candidate prognostic biomarkers. Notable putative identities of candidate prognostic biomarkers include ethanolamine, C20:4 anandamide phosphate, progesterone, various androgens (5-α-dihydrotestosterone, androsterone, etiocholanolone, and epiandrosterone), betaine aldehyde, inflammatory lipids (eicosapentaenoic acid, linoleic acid, and stearolic acid), and choline. Our exploratory data support metabolic reprogramming in early ADPKD and demonstrate the ability of liquid chromatography-mass spectrometry-based global metabolomic profiling to detect metabolic pathway alterations as new therapeutic targets and biomarkers for early diagnosis and tracking disease progression of ADPKD.NEW & NOTEWORTHY To our knowledge, this study is the first to generate urinary global metabolomic profiles from individuals with early-stage ADPKD with preserved renal function for biomarker discovery. The exploratory dataset reveals metabolic pathway alterations that may be responsible for early cystogenesis and rapid disease progression and may be potential therapeutic targets and pathway sources for candidate biomarkers. From these results, we generated a panel of candidate diagnostic and prognostic biomarkers of early-stage ADPKD for future validation.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
期刊最新文献
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