WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis
Introduction: Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI...
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Elsevier
2025-05-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224002522 |
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| author | Ran You Yanwei Li Yuteng Jiang Dandan Hu Menglei Gu Wei Zhou Shengnan Zhang Mi Bai Yunwen Yang Yue Zhang Songming Huang Zhanjun Jia Aihua Zhang |
| author_facet | Ran You Yanwei Li Yuteng Jiang Dandan Hu Menglei Gu Wei Zhou Shengnan Zhang Mi Bai Yunwen Yang Yue Zhang Songming Huang Zhanjun Jia Aihua Zhang |
| author_sort | Ran You |
| collection | DOAJ |
| description | Introduction: Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. Objectives: We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. Methods: We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2′s implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. Results: In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin’s protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells. Conclusion: Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI. |
| format | Article |
| id | doaj-art-2486c659300a4fa3bf955f38039d412f |
| institution | DOAJ |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-2486c659300a4fa3bf955f38039d412f2025-08-20T03:14:01ZengElsevierJournal of Advanced Research2090-12322025-05-017147148510.1016/j.jare.2024.06.015WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axisRan You0Yanwei Li1Yuteng Jiang2Dandan Hu3Menglei Gu4Wei Zhou5Shengnan Zhang6Mi Bai7Yunwen Yang8Yue Zhang9Songming Huang10Zhanjun Jia11Aihua Zhang12Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China; School of Medicine, Southeast University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; School of Medicine, Southeast University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China; Corresponding authors at: Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China; School of Medicine, Southeast University, Nanjing, China; Corresponding authors at: Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.Introduction: Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated. Objectives: We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study. Methods: We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2′s implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism. Results: In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin’s protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells. Conclusion: Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI.http://www.sciencedirect.com/science/article/pii/S2090123224002522WWP2CDC20AutophagyAcute kidney injuryTubular epithelial cells |
| spellingShingle | Ran You Yanwei Li Yuteng Jiang Dandan Hu Menglei Gu Wei Zhou Shengnan Zhang Mi Bai Yunwen Yang Yue Zhang Songming Huang Zhanjun Jia Aihua Zhang WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis Journal of Advanced Research WWP2 CDC20 Autophagy Acute kidney injury Tubular epithelial cells |
| title | WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis |
| title_full | WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis |
| title_fullStr | WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis |
| title_full_unstemmed | WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis |
| title_short | WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis |
| title_sort | wwp2 deletion aggravates acute kidney injury by targeting cdc20 autophagy axis |
| topic | WWP2 CDC20 Autophagy Acute kidney injury Tubular epithelial cells |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224002522 |
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