Cai Aimin, Shen Dingchao, Xiong Qiushuang, Ding Jie, Ding Yang, Lin Xinlu, Chen Lijia, Yao Qing, Lin Guangyong, Chen Ruijie, Ganapathy Vadivel, Kou Longfa
Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2025 Jan 20;15:1463673. doi: 10.3389/fphar.2024.1463673. eCollection 2024.
Diabetic nephropathy (DN), a major complication of diabetes, presents with poor clinical outcomes and affects patients throughout their lifetime. α-Methyltryptophan (α-MT) is a blocker of the amino acid transporter. SLC6A14 and also an inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1).
In this study, we employed a nuclear magnetic resonance-based metabolomic approach to investigate the therapeutic effects of α-MT in a mouse model of DN and explore the underlying molecular mechanisms.
The results of the study demonstrated that α-MT significantly reduced the urinary excretion of albumin and creatinine, improved kidney function, and decreased renal fibrosis in mice. Metabolomic analyses of kidney tissues and urine samples indicated that mice displayed increased activity of the enzyme IDO1, and alongside pronounced metabolic disturbances. These disturbances are chiefly characterized by alterations in amino acid metabolism, energy production pathways, membrane biochemical features, and nicotinamide metabolism, all of which have been implicated in mTOR signaling and apoptotic pathways.
Administration of α-MT to mice showed evidence of IDO1 inhibition and rectification of metabolic dysfunctions with concurrent suppression of mTOR signaling and apoptosis. These findings highlight the potential of α-MT as a promising therapeutic agent for diabetic nephropathy.
糖尿病肾病（DN）是糖尿病的一种主要并发症，临床预后较差，会影响患者一生。α-甲基色氨酸（α-MT）是氨基酸转运体SLC6A14的阻断剂，也是吲哚胺2,3-双加氧酶-1（IDO1）的抑制剂。
在本研究中，我们采用基于核磁共振的代谢组学方法来研究α-MT在糖尿病肾病小鼠模型中的治疗效果，并探索其潜在的分子机制。
研究结果表明，α-MT显著降低了小鼠尿白蛋白和肌酐的排泄，改善了肾功能，并减少了肾纤维化。对肾组织和尿液样本的代谢组学分析表明，小鼠IDO1酶活性增加，同时伴有明显的代谢紊乱。这些紊乱主要表现为氨基酸代谢、能量产生途径、膜生化特征和烟酰胺代谢的改变，所有这些都与mTOR信号通路和凋亡途径有关。
给小鼠施用α-MT显示出抑制IDO1和纠正代谢功能障碍的证据，同时抑制了mTOR信号通路和细胞凋亡。这些发现突出了α-MT作为糖尿病肾病有前景的治疗药物的潜力。
