基于尿液代谢组学研究碘克沙醇损伤肾小管功能的作用机制

Study on the Mechanism of Iodixanol on Renal Tubular Function Damage Based on Urine Metabolomics

关键词:  碘克沙醇|肾小管功能|尿液|代谢组学

Key words:  iodixanol|renal tubular dysfunction|urine|metabolomics

摘要:

目的 研究使用碘克沙醇行冠脉造影后肾小管功能出现损伤患者尿液中内源性代谢物的代谢特征，分析碘克沙醇导致肾小管损伤的潜在机制。方法 选择使用碘克沙醇冠脉造影后24 h内肾小管功能正常和肾小管功能出现损伤的患者各50例，分为正常组(n=50)和损伤组(n=50)，收集其造影24 h内的晨尿尿液样本。采用超高效液相色谱串联质谱以及正交偏最小二乘法(orthogonal partial least squares，OPLS-DA)对尿液样品进行代谢分析；利用Metlin、HMDB、KEGG、MetaboAnalyst数据库考察碘克沙醇损伤肾小管功能的代谢特征。结果 鉴定出与碘克沙醇损伤肾小管功能相关的差异代谢物25种[变量权重值(variable important in projection，VIP)>1]，其中有3种代谢差异代谢物的含量显著下降(VIP>1，P<0.05)，分别为L-苯丙氨酸、L-酪氨酸、L-色氨酸。25种差异代谢物涉及的代谢通路有9条，主要为氨基酸代谢，其中Impact>0.10，P<0.05的目标代谢通路有2条，分别为苯丙氨酸、酪氨酸和色氨酸的生物合成通路及苯丙氨酸代谢通路。结论 使用碘克沙醇行冠脉造影后肾小管功能出现损伤患者的尿液代谢主要表现为氨基酸代谢紊乱，尿液中L-酪氨酸、L-苯丙氨酸、L-色氨酸含量显著下降可提示肾小管功能出现损伤。碘克沙醇相关早期肾损伤的发病机制主要是通过影响苯丙氨酸、酪氨酸和色氨酸生物合成通路，苯丙氨酸代谢通路来损伤肾小管，进而影响其功能。

Abstract:

OBJECTIVE To study the metabolic characteristics of endogenous metabolites in urine of patients with renal tubular function impairment after coronary angiography using iodixanol and to analyze the potential mechanism of renal tubular damage caused by iodixanol. METHODS Patients with normal renal tubular function and with renal tubular function injury after 24 h of coronary angiography with iodixanol were divided into the normal group(n=50) and the injured group(n=50), their morning urine samples were collected 24 h after angiography. The urine samples were metabolically analyzed using ultra high performance liquid chromatography-mass spectrometry combined with orthogonal partial least squares(OPLS-DA), and the metabolic characteristics of renal tubule function injured by iodoxazole were searched by Metlin, HMDB, KEGG and MetaboAnalyst databases. RESULTS The 25 metabolites[(variable important in projection, VIP)>1] related to the renal tubular function damage by iodixanol were identified, and the content of 3 metabolites with metabolic differences significantly decreased(VIP>1, P<0.05), which were L-phenylalanine, L-tyrosine and L-tryptophan respectively. There were 9 metabolic pathways involved in 25 different metabolites, mainly amino acid metabolism. Among them, there were 2 target metabolic pathways(Impact>0.10, P<0.05), which were phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism. CONCLUSION The significant decrease of L-phenylalanine, L-tyrosine and L-tryptophan in urine after coronary angiography with iodixanol may indicate the injury of renal tubular function. The urine metabolism of patients with renal tubular function injury after coronary angiography with iodixanol is mainly manifested as amino acid metabolism disorder, and iodixanol damages renal tubular function mainly by affecting phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism.