Abstract: SA-PO124
Adiponectin Alleviates AKI-Related Pyroptosis and Inflammation by Accelerating NLRP3 Degradation
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Shao, Baoyi, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Wang, Jianan, Anhui Medical University, Hefei, Anhui, China
- Li, Haidi, Anhui Medical University, Hefei, Anhui, China
- Guo, Jianbo, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Wang, Yifan, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Chen, Hai-Yong, School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Group or Team Name
- School of Chinese Medicine.
Background
Adiponectin (APN), an adipose tissue-derived hormone, exhibits multifaceted effects on various tissues. The role of adiponectin in acute kidney injury (AKI) remains largely unclear. This study investigated whether adiponectin mitigates AKI by inhibiting pyroptosis and inflammation through the NLRP3/GSDMD-mediated pathway.
Methods
The levels of APN were tested in AKI-induced mouse models. Adiponectin knockout (KO) and wild-type (WT) mice were induced into AKI by injection of cisplatin, lipopolysaccharide, or folic acid. The effects of AdipoRon, an APN receptor agonist, were observed in three AKI models in vivo and in cisplatin-induced mouse tubular epithelial cells (mTECs). The role of AMPK in the renoprotective effects of APN was investigated and the relationship between AMPK and NLRP3 was researched.
Results
APN decreased in different AKI models. APN deletion exacerbated AKI-induced nephrotoxicity and inflammation as indicated by increased kidney injury scores and related inflammatory factors. APN deletion promoted the activation of pyroptosis-related NLRP3/GSDMD pathway across three AKI models rather than apoptosis, necroptosis or ferroptosis as expressed by relevant executioners in vivo. AdipoRon protected against AKI-induced nephrotoxicity and inflammation by directly activating AMPK and ameliorating pyroptosis-related pathways in vivo and in vitro. The renoprotective role of AdipoRon/APN was reversed by Compound C, an AMPK inhibitor. AICAR, an activator of AMPK, reduced the protein levels of NLRP3 without significantly affecting its mRNA levels, indicating NLRP3 undergoes post-translational modifications upon AMPK activation. AICAR-mediated NLRP3 reduction was prevented by MG-132 but not chloroquine, which suggested NLRP3 might be degraded through the ubiquitin-proteasome system. Indeed, AICAR enhanced NLRP3 ubiquitination as demonstrated by western blots in ubiquitin-transfected mTECs. Co-Immunoprecipitation followed by liquid chromatography–mass spectrometry identified several potential E3 ubiquitin ligases that could interact with NLRP3 and function as downstream transcription factors of AMPK.
Conclusion
APN mitigates AKI by inhibiting pyroptosis and inflammation via AMPK/NLRP3 pathways. Targeting APN/AMPK/NLRP3 represents a novel therapeutic strategy for addressing AKI-induced nephrotoxicity and inflammation.
Funding
- Government Support – Non-U.S.