文献类型：期刊文献

英文题名：Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury

作者：Zhang, Wenjun[1,2];Guo, Chao[3];Li, Yi[4];Wang, Hao[5];Wang, Huabing[5];Wang, Yingying[1];Wu, Tingting[6];Wang, Huinan[7];Cheng, Gang[7];Man, Jiangwei[5];Chen, Siyu[5];Fu, Shengjun[5];Yang, Li[5,8,9]

第一作者：Zhang, Wenjun

通信作者：Yang, L[1]

机构：[1]Lanzhou Univ, Affiliated Hosp 2, Dept Nephrol, Lanzhou, Peoples R China;[2]Gansu Provicne Clin Res Ctr Kidney Dis, Lanzhou, Peoples R China;[3]Gansu Univ Chinese Med, Sci Res & Expt Ctr, Lanzhou, Peoples R China;[4]Lanzhou Univ, Affiliated Hosp 2, Dept Anesthesiol, Lanzhou, Peoples R China;[5]Lanzhou Univ, Affiliated Hosp 2, Dept Urol Surg, Lanzhou, Peoples R China;[6]Lanzhou Univ, Affiliated Hosp 2, Dept Funct Examinat Children, Lanzhou, Peoples R China;[7]Lanzhou Univ, Clin Med Coll 2, Lanzhou, Peoples R China;[8]Gansu Provicne Clin Res Ctr Urol, Lanzhou, Peoples R China;[9]Lanzhou Univ, Affiliated Hosp 2, Dept Urol Surg, 82 Cui Ying Gate, Lanzhou 730030, Peoples R China

第一机构：Lanzhou Univ, Affiliated Hosp 2, Dept Nephrol, Lanzhou, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Affiliated Hosp 2, Dept Urol Surg, 82 Cui Ying Gate, Lanzhou 730030, Peoples R China.

年份：2024

卷号：46

期号：1

外文期刊名：RENAL FAILURE

收录：;Scopus(收录号：2-s2.0-85189447884);WOS:【SCI-EXPANDED(收录号:WOS:001198114100001)】；

基金：This study was supported in part by grants from the Gansu Province Natural Science Foundation (#20JR10RA743), the Introducing Talent Research Project of Lanzhou University Second Hospital (#ynyjrckyzx2015-3-04), the Lanzhou Science and Technology Planning and Development Project (#2020-ZD-85), and the Cuiying Scientific and Technological Innovation Program of The Second Hospital & Clinical Medical School, Lanzhou University (#CY2023-MS-A08)

语种：英文

外文关键词：Acute kidney injury; FUNDC1; HIF-1; alpha mitophagy; roxadustat

摘要：Acute kidney injury (AKI) is associated with a high mortality rate. Pathologically, renal ischemia/reperfusion injury (RIRI) is one of the primary causes of AKI, and hypoxia-inducible factor (HIF)-1 alpha may play a defensive role in RIRI. This study assessed the role of hypoxia-inducible factor 1 alpha (HIF-1 alpha)-mediated mitophagy in protection against RIRI in vitro and in vivo. The human tubular cell line HK-2 was used to assess hypoxia/reoxygenation (H/R)-induced mitophagy through different in vitro assays, including western blotting, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reactive oxygen species (ROS) measurement. Additionally, a rat RIRI model was established for evaluation by renal histopathology, renal Doppler ultrasound, and transmission electron microscopy to confirm the in vitro data. The selective HIF-1 alpha inhibitor LW6 reduced H/R-induced mitophagy but increased H/R-induced apoptosis and ROS production. Moreover, H/R treatment enhanced expression of the FUN14 domain-containing 1 (FUNDC1) protein. Additionally, FUNDC1 overexpression reversed the effects of LW6 on the altered expression of light chain 3 (LC3) BII and voltage-dependent anion channels as well as blocked the effects of HIF-1 alpha inhibition in cells. Pretreatment of the rat RIRI model with roxadustat, a novel oral HIF-1 alpha inhibitor, led to decreased renal injury and apoptosis in vivo. In conclusion, the HIF-1 alpha/FUNDC1 signaling pathway mediates H/R-promoted renal tubular cell mitophagy, whereas inhibition of this signaling pathway protects cells from mitophagy, thus aggravating apoptosis, and ROS production. Accordingly, roxadustat may protect against RIRI-related AKI.