Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury
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-...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Renal Failure |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/0886022X.2024.2332492 |
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| author | Wenjun Zhang Chao Guo Yi Li Hao Wang Huabing Wang Yingying Wang Tingting Wu Huinan Wang Gang Cheng Jiangwei Man Siyu Chen Shengjun Fu Li Yang |
| author_facet | Wenjun Zhang Chao Guo Yi Li Hao Wang Huabing Wang Yingying Wang Tingting Wu Huinan Wang Gang Cheng Jiangwei Man Siyu Chen Shengjun Fu Li Yang |
| author_sort | Wenjun Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c421972032fa4c5ead796c48ce7ca318 |
| institution | Kabale University |
| issn | 0886-022X 1525-6049 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Renal Failure |
| spelling | doaj-art-c421972032fa4c5ead796c48ce7ca3182025-01-23T04:17:48ZengTaylor & Francis GroupRenal Failure0886-022X1525-60492024-12-0146110.1080/0886022X.2024.2332492Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injuryWenjun Zhang0Chao Guo1Yi Li2Hao Wang3Huabing Wang4Yingying Wang5Tingting Wu6Huinan Wang7Gang Cheng8Jiangwei Man9Siyu Chen10Shengjun Fu11Li Yang12Department of Nephrology, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaScientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou, ChinaDepartment of Anesthesiology, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Nephrology, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Functional Examination in Children, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaThe Second Clinical Medical College of Lanzhou University, Lanzhou, ChinaThe Second Clinical Medical College of Lanzhou University, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaDepartment of Urology Surgery, Lanzhou University Affiliated Second Hospital, Lanzhou, ChinaAcute 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.https://www.tandfonline.com/doi/10.1080/0886022X.2024.2332492Acute kidney injuryFUNDC1HIF-1α mitophagyroxadustat |
| spellingShingle | Wenjun Zhang Chao Guo Yi Li Hao Wang Huabing Wang Yingying Wang Tingting Wu Huinan Wang Gang Cheng Jiangwei Man Siyu Chen Shengjun Fu Li Yang Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury Renal Failure Acute kidney injury FUNDC1 HIF-1 α mitophagy roxadustat |
| title | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury |
| title_full | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury |
| title_fullStr | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury |
| title_full_unstemmed | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury |
| title_short | Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury |
| title_sort | mitophagy mediated by hif 1α fundc1 signaling in tubular cells protects against renal ischemia reperfusion injury |
| topic | Acute kidney injury FUNDC1 HIF-1 α mitophagy roxadustat |
| url | https://www.tandfonline.com/doi/10.1080/0886022X.2024.2332492 |
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