Nishida Sho, Ishima Tamaki, Iwami Daiki, Nagai Ryozo, Aizawa Kenichi
Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan.
Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University, Shimotsuke 329-0498, Japan.
Int J Mol Sci. 2025 Aug 5;26(15):7549. doi: 10.3390/ijms26157549.
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) remains a major contributor to late allograft dysfunction in kidney transplant recipients. Although detailed mechanisms remain incompletely understood, our previous metabolomic studies revealed disruptions in carnitine-related and redox pathways, suggesting impaired mitochondrial β-oxidation of fatty acids. To further characterize metabolic alterations associated with this condition, we conducted an untargeted lipidomic analysis of renal tissues using a murine model of TAC nephrotoxicity. TAC (1 mg/kg/day) or saline was subcutaneously administered to male ICR mice for 28 days, and kidney tissues were harvested for comprehensive lipidomic profiling. Lipidomic analysis was performed with liquid chromatography-tandem mass spectrometry ( < 0.05, = 5/group). Triacylglycerols (TGs) were the predominant lipid class identified. TAC-treated mice exhibited reduced levels of unsaturated TG species with low carbon numbers, whereas TGs with higher carbon numbers and various degrees of unsaturation were increased. All detected TGs containing docosahexaenoic acid (DHA) showed an increasing trend in TAC-treated kidneys. Although accumulation of polyunsaturated TGs has been previously observed in chronic kidney disease, the preferential increase in DHA-containing TGs appears to be a unique feature of TAC-induced nephrotoxicity. These results suggest that DHA-enriched TGs may serve as a metabolic signature of TAC nephrotoxicity and offer new insights into its pathophysiology.
他克莫司（TAC）诱导的慢性肾毒性（TAC肾毒性）仍然是肾移植受者晚期移植肾功能障碍的主要原因。尽管详细机制仍未完全了解，但我们之前的代谢组学研究揭示了肉碱相关途径和氧化还原途径的紊乱，提示脂肪酸的线粒体β氧化受损。为了进一步表征与这种情况相关的代谢改变，我们使用TAC肾毒性小鼠模型对肾组织进行了非靶向脂质组学分析。将TAC（1 mg/kg/天）或生理盐水皮下注射给雄性ICR小鼠，持续28天，然后采集肾脏组织进行全面的脂质组学分析。采用液相色谱-串联质谱法进行脂质组学分析（<0.05，每组n = 5）。三酰甘油（TGs）是鉴定出的主要脂质类别。TAC处理的小鼠中，低碳数不饱和TG种类的水平降低，而碳数较高且具有不同程度不饱和的TGs增加。在TAC处理的肾脏中，所有检测到的含二十二碳六烯酸（DHA）的TGs均呈上升趋势。虽然先前在慢性肾脏病中已观察到多不饱和TGs的蓄积，但含DHA的TGs优先增加似乎是TAC诱导的肾毒性的一个独特特征。这些结果表明，富含DHA的TGs可能作为TAC肾毒性的代谢标志物，并为其病理生理学提供新的见解。
