Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat†

IF 3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular omics Pub Date : 2023-03-20 DOI:10.1039/D3MO00015J

Xiaoe You, Baochun Guo, Zhen Wang, Hualin Ma, Lixia Liu, Ru Zhou, Yaxuan Zheng and Xinzhou Zhang

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Abstract

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS–MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

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肾性贫血患者尿液的综合蛋白质组学和代谢组学分析揭示了罗沙司他†的分子机制

罗沙司他(FG-4592)是一种缺氧诱导因子脯氨酸羟化酶抑制剂(HIF-PHI)，用于慢性肾脏疾病相关的低血红蛋白患者。由于各种hif介导的适应性反应，FG-4592在治疗各种疾病方面引起了极大的兴趣。然而，由于缺乏对其潜在机制的了解，罗沙司他的临床应用仍然有限。本研究采用无标记定量液相色谱串联质谱(LC-MS-MS)蛋白质组学和非靶向代谢组学方法，研究了罗沙他治疗前后肾性贫血患者尿液中蛋白质和代谢物的变化。通过平行反应监测(PRM)对结果进行了验证。肾性贫血患者尿液样本经罗沙司他治疗后，共有46种蛋白(包括15种上调蛋白和31种下调蛋白)和207种代谢物发生显著改变。然后，用PRM进一步验证改变后的蛋白。最后，蛋白质组学结合代谢组学分析显示，罗沙他治疗改变的主要途径是Ras信号通路、半胱氨酸和蛋氨酸代谢、精氨酸和脯氨酸代谢以及胆固醇代谢。多组学分析显示，罗沙司他可改变蛋白质表达，逆转潜在的代谢变化，在临床实践中发挥降压、脂质代谢调节和肾保护作用。

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来源期刊

Molecular omics Biochemistry, Genetics and Molecular Biology-Biochemistry

CiteScore

5.40

自引率

3.40%

发文量

期刊介绍： Molecular Omics publishes high-quality research from across the -omics sciences. Topics include, but are not limited to: -omics studies to gain mechanistic insight into biological processes – for example, determining the mode of action of a drug or the basis of a particular phenotype, such as drought tolerance -omics studies for clinical applications with validation, such as finding biomarkers for diagnostics or potential new drug targets -omics studies looking at the sub-cellular make-up of cells – for example, the subcellular localisation of certain proteins or post-translational modifications or new imaging techniques -studies presenting new methods and tools to support omics studies, including new spectroscopic/chromatographic techniques, chip-based/array technologies and new classification/data analysis techniques. New methods should be proven and demonstrate an advance in the field. Molecular Omics only accepts articles of high importance and interest that provide significant new insight into important chemical or biological problems. This could be fundamental research that significantly increases understanding or research that demonstrates clear functional benefits. Papers reporting new results that could be routinely predicted, do not show a significant improvement over known research, or are of interest only to the specialist in the area are not suitable for publication in Molecular Omics.