Tran Melanie, Jiao Baihai, Du Hao, Zhou Dong, Yechoor Vijay, Wang Yanlin
Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.
Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA.
Int J Biol Sci. 2025 Jan 1;21(2):565-578. doi: 10.7150/ijbs.104335. eCollection 2025.
Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1 mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1 mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.
顺铂被广泛用于实体瘤的治疗，其抗肿瘤作用已得到充分证实。然而，顺铂给药的一个已知并发症是急性肾损伤（AKI）。在本研究中，我们研究了TEA结构域家族成员1（TEAD1）在顺铂诱导的AKI发病机制中的作用。在顺铂诱导的AKI肾脏的肾小管上皮细胞中，TEAD1表达上调。用顺铂处理的TEAD1基因敲除小鼠（TEAD1）出现肾小管细胞损伤和肾功能受损。相比之下，用顺铂处理的近端小管特异性TEAD1基因敲除（TEAD1）小鼠肾小管细胞损伤加重，肾功能障碍。此外，与用顺铂处理的TEAD1小鼠相比，用顺铂处理的TEAD1小鼠坏死性凋亡细胞死亡和炎症反应增强。与用顺铂处理的对照细胞相比，在小鼠肾小管上皮细胞中敲低TEAD1显示细胞内ROS水平升高、ATP产生减少和线粒体生物能量学受损。机制上，TEAD1与过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）相互作用，PGC-1α是线粒体生物发生的主要调节因子，可促进线粒体功能。综上所述，我们的结果表明TEAD1通过调节坏死性凋亡和炎症在顺铂诱导的AKI发病机制中起重要作用，这与线粒体代谢有关。因此，TEAD1可能是顺铂诱导的AKI的一个新的治疗靶点。
