INSERM UMR 1248, IPPRITT, Limoges, France; CHU Tours, Laboratory of Biochemistry and Molecular Biology, Tours, France; FHU SUPORT, Limoges, Poitiers, Tours, France.
CHU Tours, Laboratory of Biochemistry and Molecular Biology, Tours, France.
Pharmacol Res. 2018 Mar;129:34-43. doi: 10.1016/j.phrs.2017.12.032. Epub 2018 Jan 6.
Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.
管状细胞是肾移植中缺血再灌注（I/R）损伤的主要靶标。这些细胞内发生的炎症和代谢紊乱本身是有害的，但也有利于继发性事件，如免疫反应的激活。如果要定义相关的生物标志物或制定有针对性的治疗干预措施，深入了解调节管状细胞对 I/R 反应的机制至关重要。由于氧化损伤被证明是病理生理机制的核心，因此广泛研究了 I/R 对近端管状细胞代谢的影响，而不是其对近端管状细胞膜转运体的表达和活性的影响。然而，在缺血和再灌注期间，转运体的时间调节似乎起着核心作用，不仅在诱导细胞损伤方面，而且在移植物功能恢复方面也是如此。细胞模型或各种生物流体中的代谢组学有可能提供 I/R 生化后果的全貌。在 I/R 实验模型或移植患者中进行的代谢组学研究确实检索到了属于特别受影响途径的代谢物。有趣的是，它们还表明代谢紊乱和转运体活性之间存在非常密切的相互作用。除了有助于选择诊断生物标志物外，此类分析还有助于确定新的药理学靶点，并为未来制定创新的肾脏保护策略。尽管已经长期评估了各种治疗方法来预防或治疗 I/R 损伤，但代谢组学已帮助识别出一些新的方法，与膜转运体相关的方法似乎特别有意义。然而，考虑到 I/R 在肾移植中的非常复杂和多因素的影响，如果要预防或限制其有害后果，必须遵循所有途径。
