Xue Xian, Zhu Xingwen, Zhou Lu, Sun Xiaoli, Gu Mengru, Liang Yan, Tan Mengzhu, Hou Qing, Wang Sudan, Dai Chunsun
Center for Kidney Disease, The 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Department of Clinical Genetics, The 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Kidney Dis (Basel). 2024 Aug 19;10(6):421-435. doi: 10.1159/000540973. eCollection 2024 Dec.
Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling pathway effector, maintains the balance of cell proliferation, differentiation, and death. However, the role of TAZ in tubular cell survival and acute kidney injury (AKI) remains largely unknown.
We used the RNA-seq database, Western blot, and immunohistochemistry to examine TAZ expression in kidneys from cisplatin-induced AKI. We generated tubular-specific TAZ knockout mice to assess the role of TAZ in cisplatin-induced renal toxicity. Immunoprecipitation-mass spectrometry followed standard procedures.
TAZ was activated in tubular cells in kidneys injected with cisplatin. Conditional deletion of TAZ in tubular cells confers ferroptosis resistance and protects kidneys from cisplatin-induced AKI, whereas overexpression of TAZ(S89A) exacerbates cisplatin-induced ferroptosis. Inhibition of ferroptosis with ferrostatin-1 potently preserves renal function and alleviates morphological injury and tubular cell ferroptosis induced by cisplatin. Mechanistically, in a PPARδ-dependent manner, but not TEAD, TAZ reduces the expression of glutathione peroxidase 4 (GPX4), thus exacerbating cisplatin-induced ferroptosis.
Our findings show that cisplatin-induced AKI and tubular cell ferroptosis are mediated by TAZ-PPARδ interaction through regulation of GPX4, highlighting TAZ as a potential therapeutic candidate for AKI.
含PDZ结合基序的转录共激活因子（TAZ）是一种Hippo信号通路效应因子，可维持细胞增殖、分化和死亡的平衡。然而，TAZ在肾小管细胞存活和急性肾损伤（AKI）中的作用仍 largely未知。
我们使用RNA测序数据库、蛋白质免疫印迹法和免疫组织化学法检测顺铂诱导的AKI小鼠肾脏中TAZ的表达。我们构建了肾小管特异性TAZ基因敲除小鼠，以评估TAZ在顺铂诱导的肾毒性中的作用。免疫沉淀-质谱分析遵循标准程序。
在注射顺铂的小鼠肾脏中，肾小管细胞中的TAZ被激活。肾小管细胞中TAZ的条件性缺失赋予了铁死亡抗性，并保护肾脏免受顺铂诱导的AKI，而TAZ（S89A）的过表达则加剧了顺铂诱导的铁死亡。用铁死亡抑制剂Ferrostatin-1抑制铁死亡可有效保护肾功能，并减轻顺铂诱导的形态学损伤和肾小管细胞铁死亡。机制上，TAZ以PPARδ依赖而非TEAD依赖的方式降低谷胱甘肽过氧化物酶4（GPX4）的表达，从而加剧顺铂诱导的铁死亡。
我们的研究结果表明，顺铂诱导的AKI和肾小管细胞铁死亡是由TAZ-PPARδ相互作用通过调节GPX4介导的，这突出了TAZ作为AKI潜在治疗靶点的可能性。
