Supplementary Material for: Proteomics to metabolomics: A new insight into the pathogenesis of hypertensive nephropathy

Abstract Background: Hypertensive nephropathy (HN) is a high burden disorder and a leading cause of end-stage renal disorder. In spite of huge investigations, the underlying mechanisms are yet largely unknown. Systems biology is a promising approach to provide a comprehensive insight towards this complex disorder. Methods: Protein expression profiles of kidney tubule and cortex sub-compartments were retrieved from the PRIDE database and the quality of the datasets were assessed using principal component analysis (PCA) and hierarchical clustering. Differentially expressed proteins (DEPs) were detected and their attributed metabolites were enriched and their interactions were assessed in multi-layer networks. Moreover, considering the DEPs and the predicted metabolites, key biomedical phenomena with a leading role in HN pathogenesis were proposed. Results: Amino acid and purine metabolisms are the most prominent alteration in kidney cortex whereas dysregulation of energy hemostasis is a key pathogenic mechanism in tubule. Besides, actin cytoskeleton disorganization is an enriched pathway in both anatomical areas. Conclusion: The proteomics profiles of kidney sub-compartments were analyzed using a top-down approach to infer the main pathogenic processes. The constructed holistic map of HN can be exploited to propose novel therapeutic strategies. Keywords: Hypertensive nephropathy, Proteomics, Metabolomics, Systems biology

摘要
背景：高血压肾病（Hypertensive nephropathy, HN）是一种高负担疾病，也是终末期肾病的主要诱因。尽管已有大量相关研究，其潜在发病机制仍未完全明确。系统生物学（Systems biology）为解析这一复杂疾病提供了极具前景的全面研究路径。
方法：本研究从PRIDE数据库（PRIDE database）获取肾小管与肾皮质亚分区的蛋白质表达谱，并通过主成分分析（principal component analysis, PCA）与层次聚类对数据集质量进行评估。检测得到差异表达蛋白（Differentially expressed proteins, DEPs）后，对其关联的代谢物进行富集分析，并通过多层网络解析二者的相互作用关系。此外，结合差异表达蛋白与预测得到的代谢物，本研究提出了在高血压肾病发病机制中发挥核心作用的关键生物医学现象。
结果：研究显示，肾皮质中最显著的代谢紊乱为氨基酸与嘌呤代谢异常，而肾小管的关键致病机制则为能量稳态失调；此外，肌动蛋白细胞骨架紊乱是两个解剖分区共同富集的通路。
结论：本研究通过自上而下的方法分析了肾脏亚分区的蛋白质组学特征，进而推导得到高血压肾病的主要致病过程。所构建的高血压肾病全景图谱可用于提出全新的治疗策略。
关键词：高血压肾病、蛋白质组学、代谢组学、系统生物学