急性肾损伤向慢性肾脏病转化的肾脏脂质代谢特征

Lipid signatures of acute kidney injury to chronic kidney disease transition

目的 探讨急性肾损伤(acute kidney injury,AKI)向慢性肾脏病(chronic kidney disease,CKD)转化中肾组织脂质代谢特征。方法 通过肾脏缺血再灌注损伤(ischemia-reperfusion injury,IRI)(双侧肾动脉夹闭30 min)构建AKI向CKD转化的小鼠模型。取第2天、第14天及第28天小鼠肾脏组织,通过超高效液相色谱串联质谱检测不同时间点IRI小鼠与假手术组小鼠肾脏脂质代谢,分析各组间脂质代谢差异,通过京都基因和基因组百科全书富集化分析揭示AKI向CKD转化脂质代谢所参与的重要通路。结果 IRI小鼠第2天血肌酐较假手术组明显升高,并伴有肾小管明显急性损伤;在第14天和28天时,IRI小鼠肾脏纤维化程度明显加重。我们总共检测到1715种脂质代谢物。代谢物主要成分分析显示,不仅IRI小鼠在各个时间点均与假手术组显示出不同脂质代谢特征,而且IRI小鼠不同时间点间的脂质代谢也存在较大差异。在AKI阶段,肾脏脂质代谢特征以中性脂质蓄积最为明显,而在IRI后14 d和28 d时,改变最明显的脂质代谢物为甘油磷脂及鞘脂。在IRI 28 d时,下调甘油磷脂(186种)种类多于上调甘油磷脂(132种)。在上调甘油磷脂中,烯基(乙烯基)醚-磷脂酰乙醇胺最为明显,而在下调磷脂中,磷脂酰甘油最为明显。京都基因和基因组百科全书富集化分析显示,在此阶段甘油磷脂代谢通路下调最为显著。结论 我们的研究显示,AKI向CKD转化整个过程中,肾脏脂质代谢发生了显著变化,并且急性期与慢性期的脂质组学同样存在明显差异。甘油磷脂,尤其是烯基(乙烯基)醚-磷脂酰乙醇胺下调、磷脂酰甘油上调可能在AKI向CKD转化后期肾脏纤维化中发挥了重要作用。我们的研究为未来研究脂质代谢在AKI向CKD转化中的作用与机制提供了基础。

Objective To explore lipid signatures of renal tissue in acute kidney injury(AKI) and AKI-to-CKD transition by untargeted lipidomics.Methods Ischemia-reperfusion injury(IRI) mice were subjected to bilateral renal pedicle clamping for 30 min.A murine model was established for longitudinally examining CKD progression after AKI and analyzing renal lipid metabolites by ultra-high performance liquid chromatography-tandem mass spectrometry.Results The levels of serum creatinine(Scr)and blood urea nitrogen(BUN) were significantly elevated after IRI and acute tubular injury score rose obviously at Day 2 post-IRI.The levels of Scr and BUN declined at Day 14/28 post-IRI and yet failed to completely return to baseline with severe renal interstitial fibrosis.A total of 1715 lipid metabolites were identified.Marked differences existed in renal lipid metabolic profiles between IRI and sham-operated mice at the corresponding timepoint.And there were also distinct lipids characteristic among IRI groups.In AKI stage,renal neutral lipid accumulation was most pronounced.In AKI-to-CKD transition stage,the most distinguished features of lipid profile were changes of glycerophospholipids and Sphingolipids.At Day 28 post-IRI,the number of decreased glycerophospholipid was more than increased glycerophospholipid.The most pronounced increase of alkenyl(vinyl) ether-phosphatidylethanolamine and the most pronounced decrease of phosphatidylglycerol occurred at Day 28 post-IRI.KEGG pathway enrichment also indicated glycerophospholipid metabolism was a predominant pathway during AKI-to-CKD transition.Conclusion Our study has revealed renal lipid signatures in the whole process of AKI to CKD transition.Glycerophospholipid,especially alkenyl(vinyl) ether-phosphatidylethanolamine and phosphatidylglycerol,might be an important lipid involved in AKI to CKD transition.It may facilitate the future study of pathogenesis and mechanism involved in AKI-to-CKD transition.