Tian Zhangyu, Wu Yiming, Yi Bin, Li Ling, Liu Yan, Zhang Hao, Li Aimei
Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, Changsha, Hunan, China.
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Autophagy. 2025 Sep;21(9):1927-1944. doi: 10.1080/15548627.2025.2483598. Epub 2025 Apr 4.
The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI. AAV: adeno-associated virus; AKI: acute kidney injury; CQ: chloroquine; ESCRT: endosomal sorting complex required for transport; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PAS: periodic acid Schiff; PTECs: proximal renal tubule epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.
化疗药物顺铂被广泛用于治疗各种实体瘤。然而，其临床应用受到肾毒性的限制。尽管众多研究已证明增强巨自噬/自噬在减轻顺铂诱导的急性肾损伤（AKI）方面具有潜力，但肾小管损伤期间自噬过程的动态变化仍有待阐明。在我们的研究中，我们观察到顺铂处理导致小鼠肾小管上皮细胞和BUMPT细胞中LC3-II、GABARAPL1、SQSTM1/p62和NBR1的表达增加。此外，在超微结构上，AKI小鼠中自噬泡大量积累。这些发现表明顺铂诱导的AKI导致肾小管细胞内自噬流受损。此外，发现顺铂处理后LGALS3（半乳糖凝集素3）在溶酶体中富集，揭示了自噬功能障碍与溶酶体膜完整性受损之间的密切关联。鉴于溶酶体的有害内容物，溶酶体膜通透性必须迅速解决。我们的研究结果表明，ESCRT III亚基CHMP4A介导的溶酶体膜修复在顺铂诱导的AKI模型中显著改善自噬缺陷并防止溶酶体损伤诱导的细胞死亡。总之，我们的研究表明ESCRT III介导的溶酶体修复可减轻顺铂诱导的细胞凋亡并恢复肾小管上皮细胞中的正常自噬功能。该机制对顺铂诱导的AKI起保护作用。AAV：腺相关病毒；AKI：急性肾损伤；CQ：氯喹；ESCRT：转运所需的内体分选复合物；LMP：溶酶体膜通透性；MAP1LC3/LC3：微管相关蛋白1轻链3；MTOR：雷帕霉素激酶的机制性靶点；PAS：过碘酸希夫；PTECs：近端肾小管上皮细胞；TEM：透射电子显微镜；TUNEL：末端脱氧核苷酸转移酶dUTP缺口末端标记
