Abstract: SA-PO0249
Dynamic Properties of Stress Granules Involved in AKI-to-CKD Transition by Regulating MDM2 Subcellular Localization
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhu, Jinchai, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China
- Su, Hua, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China
Background
Preventing the transition from acute kidney injury to chronic kidney disease (AKI-CKD) remains a clinical challenge. Stress granules (SGs) formed under stress, help cells survive by regulating cytoplasmic signaling and nuclear processes. Normally, SGs disassembled within hours and aberrant SGs dynamics is implicated in various diseases, but its role in AKI-CKD is unclear. We previously showed that abnormal subcellular distribution of MDM2 (murine double minute 2) participates in AKI-CKD. Yet whether SGs assembly regulates MDM2 localization is unknown.
Methods
Cisplatin (CP) and ischemia-reperfusion injury (IRI) were used to induce AKI and AKI-CKD mouse models. In vitro, HK-2 cells were treated with CP or hypoxia/reoxygenation. Immunofluorescence (IF), co-immunoprecipitation (Co-IP), western blot and RNP granule isolation were performed. SGs formation was blocked by G3BP1 knockdown or promoted by perillaldehyde (PAE), while SGs disassembly was induced by integrated stress response inhibitor ISRIB.
Results
Firstly, in AKI mouse models, IF showed numerous G3BP1-labeled SGs formed in proximal tubular epithelial cells. In vitro, CP-induced SGs peaked at 24 h, and nearly disassembled after 24 h recovery. Hypoxia (6 h) initiated SGs formation, which disappeared after 6 h reoxygenation. MDM2 co-localized with SGs (IF), moreover Co-IP and western blot of RNP granules confirmed their interaction. PAE, a promoter of SGs assembly, enhanced MDM2 localization within SGs and suppressed MDM2-NF-κB-mediated inflammation, whereas G3BP1 knockdown abolished these effects. Secondly, in AKI-CKD mouse models (repeated CP 8 mg/kg/week or IRI 35 min), SGs persisted on days 14 and 28 with progressive fibrosis. In vitro, repeated CP also disturbed proper SGs disassembly. Previously, we found repeated CP redistributed MDM2 from nucleus to cytoplasm. Here, chronic CP exposure impaired SGs disassembly, trapping MDM2 within SGs and blocking its nuclear import. Furthermore, ISRIB promoted SGs disassembly, restored nuclear MDM2 distribution, and eventually inhibited p53-associated cell cycle arrest.
Conclusion
SGs regulate MDM2 localization to play dual roles in AKI-CKD. In acute phase, SGs sequester MDM2 to halt cytoplasmic inflammation. Later, persistent SGs retain MDM2, reducing nuclear MDM2-mediated p53 inhibition and promoting kidney fibrosis. Modulating SGs dynamics is a promising strategy to prevent AKI-CKD.
Acknowledgment
This work was supported by National Natural Science Foundation of China (No. 8257036257).
Funding
- Government Support – Non-U.S.