Zheng Fen, Lei Jian-Zhen, Wang Jing-Xiao, Xu Xiao-Yu, Zhou Bing, Ge Rui, Dai Min, Dong Hong-Ke, Wu Nan, Li Yue-Hua, Zhu Guo-Qing, Zhou Ye-Bo
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China; The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Free Radic Biol Med. 2025 Feb 1;227:296-311. doi: 10.1016/j.freeradbiomed.2024.12.024. Epub 2024 Dec 9.
Ferroptosis is a type of non-apoptotic regulated cell death characterized by iron accumulation and lipid peroxidation. Cisplatin is an effective chemotherapy drug with several serious side effects including acute kidney injury (AKI). Asprosin is a peptide contributing to metabolism regulation and metabolic disorders. This study aimed to determine the role and mechanism of asprosin in AKI. Cisplatin was used to induce cell damage in mouse renal tubular epithelial (TCMK-1) cells and AKI in C57BL/6 mice. Cisplatin caused asprosin upregulation in cisplatin-treated TCMK-1 cells and mice. In TCMK-1 cells, asprosin overexpression led to iron overload and lipid peroxidation, while asprosin knockdown attenuated cisplatin-induced iron overload, lipid peroxidation and ferroptosis. Exogenous asprosin promoted cell damage and ferroptosis, which were attenuated by ferroptosis inhibitors. Asprosin-induced iron overload, lipid peroxidation, cell damage and SMAD1/5/8 phosphorylation were prevented by bone morphogenetic protein (BMP) type I receptor inhibitor. Integrin antagonist prevented asprosin-induced SMAD1/5/8 phosphorylation, and asprosin can specifically bind to integrin β3. Inhibition of integrin β3 reduced the asprosin-induced increases in Fe and MDA levels. Asprosin knockdown relieved cisplatin-induced hepcidin upregulation, while hepcidin knockdown attenuated asprosin-induced iron overload, lipid peroxidation and ferroptosis. In cisplatin-induced AKI mice, specific knockdown of asprosin in the kidney not only attenuated renal dysfunction and damage, but also alleviated iron overload, lipid peroxidation and ferroptosis. These results indicated that excessively increased asprosin promotes TCMK-1 cells ferroptosis and damage via integrin β3/BMP/hepcidin-mediated iron overload and lipid peroxidation. Silencing of asprosin attenuates renal injury and dysfunction in cisplatin-induced AKI by inhibiting ferroptosis.
铁死亡是一种非凋亡性的程序性细胞死亡，其特征是铁积累和脂质过氧化。顺铂是一种有效的化疗药物，但有包括急性肾损伤（AKI）在内的几种严重副作用。Asprosin是一种参与代谢调节和代谢紊乱的肽。本研究旨在确定Asprosin在AKI中的作用和机制。使用顺铂诱导小鼠肾小管上皮（TCMK-1）细胞损伤和C57BL/6小鼠的AKI。顺铂导致顺铂处理的TCMK-1细胞和小鼠中Asprosin上调。在TCMK-1细胞中，Asprosin过表达导致铁过载和脂质过氧化，而敲低Asprosin可减轻顺铂诱导的铁过载、脂质过氧化和铁死亡。外源性Asprosin促进细胞损伤和铁死亡，而铁死亡抑制剂可减弱这种作用。骨形态发生蛋白（BMP）I型受体抑制剂可阻止Asprosin诱导的铁过载、脂质过氧化、细胞损伤和SMAD1/5/8磷酸化。整合素拮抗剂可阻止Asprosin诱导的SMAD1/5/8磷酸化，且Asprosin可特异性结合整合素β3。抑制整合素β3可降低Asprosin诱导的铁和丙二醛水平升高。敲低Asprosin可减轻顺铂诱导的铁调素上调，而敲低铁调素可减弱Asprosin诱导的铁过载、脂质过氧化和铁死亡。在顺铂诱导的AKI小鼠中，肾脏中特异性敲低Asprosin不仅减轻了肾功能障碍和损伤，还减轻了铁过载、脂质过氧化和铁死亡。这些结果表明，过度增加的Asprosin通过整合素β3/BMP/铁调素介导的铁过载和脂质过氧化促进TCMK-1细胞铁死亡和损伤。敲低Asprosin可通过抑制铁死亡减轻顺铂诱导的AKI中的肾损伤和功能障碍。
