https://scholars.lib.ntu.edu.tw/handle/123456789/641462
標題: | Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury | 作者: | Lin, Hugo Y-H Liang, Chan-Jung Yang, Ming-Yu Chen, Phang-Lang Wang, Tzu-Ming Chen, Yen-Hua Shih, Yao-Hsiang Liu, Wangta Chiu, Chien-Chih CHIH-KANG CHIANG Lin, Chang-Shen Lin, Han-Chen |
關鍵字: | AKI; ATP synthase; Maleic acid; Mitochondria | 公開日期: | 28-一月-2024 | 出版社: | Springer | 來源出版物: | Apoptosis : an international journal on programmed cell death | 摘要: | Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641462 | ISSN: | 13608185 | DOI: | 10.1007/s10495-023-01897-3 |
顯示於: | 毒理學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。