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Abstract
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)-1α may play a defensive role in RIRI. This study assessed the role of hypoxia-inducible factor 1α (HIF-1α)-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-1α 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-1α inhibition in cells. Pretreatment of the rat RIRI model with roxadustat, a novel oral HIF-1α inhibitor, led to decreased renal injury and apoptosis in vivo. In conclusion, the HIF-1α/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.
Acknowledgements
We thank Medjaden Inc. for editing this manuscript.
Author contributions
WZ and LY conceived and designed the experiments; CG prepared the manuscript; YL, HW, TW, HBW, YW, HNW, and GC performed the experiments; SC, JM, and SF analyzed the data. All authors contributed to the manuscript revision and approved the submitted version.
Ethical approval
All experiments were approved by the Ethics Committee of Lanzhou University Second Hospital (ID #D2022-045) and performed according to the Chinese Council on Animal Care guidelines. Additionally, this study is reported following the ARRIVE guidelines.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets generated and analyzed during the current study are not publicly available, because none of the data types required uploading to a public repository. However, they are available from the corresponding author upon reasonable request.