DiMartino Samaneh, Revelo Monica P, Mallipattu Sandeep K, Piret Sian E
Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, New York, United States.
Department of Pathology, University of Utah, Salt Lake City, Utah, United States.
Am J Physiol Renal Physiol. 2025 Jan 1;328(1):F152-F163. doi: 10.1152/ajprenal.00260.2024. Epub 2024 Dec 9.
Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD), and there are currently no therapies for AKI. Proximal tubules (PTs) are particularly susceptible to AKI, due to nephrotoxins such as aristolochic acid I (AAI). Normal PTs use fatty acid oxidation and branched chain amino acid (BCAA; valine, leucine, and isoleucine) catabolism to generate ATP; however, in AKI, these pathways are downregulated. Our aim was to investigate the utility of a pharmacological activator of BCAA catabolism, BT2, in preventing nephrotoxic AKI. Mice were administered two injections of AAI 3 days apart to induce AKI, with or without daily BT2 treatment. Mice treated with BT2 had significantly protected kidney function (reduced serum creatinine and urea nitrogen), reduced histological injury, preservation of PT (Lotus lectin staining), and less PT injury (cytokeratin-20 staining) and inflammatory gene expression compared with mice with AAI alone. Mice with AKI had increased circulating BCAA and accumulation of BCAA in the kidney cortex. Leucine is a potent activator of the mechanistic target of rapamycin complex 1 (mTORC1) signaling, and mTORC1 signaling was activated in mice treated with AAI. However, BT2 reduced kidney cortical BCAA accumulation and attenuated the mTORC1 signaling. In vitro, injured primary PT cells had compromised mitochondrial bioenergetics, but cells treated with AAI + BT2 had partially restored mitochondrial bioenergetics and improved injury markers compared with cells treated with AAI alone. Thus, pharmacological activation of BCAA catabolism using BT2 attenuated nephrotoxic AKI in mice. This study explored the effects of pharmacological activation of branched chain amino acid (BCAA) catabolism using BT2 to prevent nephrotoxic acute kidney injury (AKI) in mice. Our results indicate that activation of BCAA catabolism protects against nephrotoxic AKI, in association with reduced BCAA accumulation, reduced mammalian target of rapamycin protein complex 1 signaling, and improved mitochondrial bioenergetics.
急性肾损伤（AKI）是慢性肾脏病（CKD）的主要危险因素，目前尚无针对AKI的治疗方法。近端肾小管（PTs）对AKI尤为敏感，这是由于诸如马兜铃酸I（AAI）等肾毒素的作用。正常的PTs利用脂肪酸氧化和支链氨基酸（BCAA；缬氨酸、亮氨酸和异亮氨酸）分解代谢来生成ATP；然而，在AKI中，这些途径会下调。我们的目的是研究BCAA分解代谢的药理激活剂BT2在预防肾毒性AKI中的效用。给小鼠每隔3天注射两次AAI以诱导AKI，同时给予或不给予每日BT2治疗。与仅接受AAI的小鼠相比，接受BT2治疗的小鼠的肾功能得到显著保护（血清肌酐和尿素氮降低），组织学损伤减轻，PT得以保留（莲花凝集素染色），PT损伤（细胞角蛋白-20染色）和炎症基因表达减少。患有AKI的小鼠循环中的BCAA增加，且BCAA在肾皮质中蓄积。亮氨酸是雷帕霉素复合物1（mTORC1）信号传导机制靶点的强效激活剂，在用AAI治疗的小鼠中mTORC1信号被激活。然而，BT2减少了肾皮质中BCAA的蓄积并减弱了mTORC1信号。在体外，受损的原代PT细胞的线粒体生物能量学受损，但与仅用AAI处理的细胞相比，用AAI + BT2处理的细胞的线粒体生物能量学部分恢复，损伤标志物得到改善。因此，使用BT2对BCAA分解代谢进行药理激活可减轻小鼠的肾毒性AKI。本研究探讨了使用BT2对支链氨基酸（BCAA）分解代谢进行药理激活以预防小鼠肾毒性急性肾损伤（AKI）的效果。我们的结果表明，BCAA分解代谢的激活可预防肾毒性AKI，这与BCAA蓄积减少、雷帕霉素蛋白复合物1信号传导的哺乳动物靶点减少以及线粒体生物能量学改善有关。
