Abstract: FR-PO0634
Mitigation of Cystogenesis in ADPKD: Role of IP1 Deficiency in Modulating the Balance Between Autophagy and Apoptosis
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Zhang, Yilin, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Ayub, Armaghan, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Shahid, Hafsa, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Qureshi, Muhammad Hamza, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Mohammadi, Ario, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Plomann, Markus, Universitat zu Koln, Cologne, NRW, Germany
- Zhou, Jing, Brigham and Women's Hospital, Boston, Massachusetts, United States
Group or Team Name
- Zhou Lab.
Background
ADPKD is the most common life-threatening monogenic disorder caused by mutations in PKD1 and PKD2 genes. While regulated cell death such as apoptosis and autophagy and their cross-talk have been studied in ADPKD, their exact processes remain not well understood.
Methods
We generated mice homozygous with an inducible mutation in Pkd1 and/or IP1 via tamoxifen injection at 3 weeks of age. Cell death pathways were screened using bioinformatics and validated in human ADPKD snRNA-seq data and Pkd1-knockout mouse proteomics. WB, IF, and IHC assessed autophagy and apoptosis. AlphaFold3 predicted protein interactions, confirmed by co-immunoprecipitation (co-IP).
Results
To understand the role of regulated cell death in ADPKD, we analyzed human ADPKD snRNA-seq data and found increased apoptosis signaling and reduced autophagy across all cell types. Proteomics of Pkd1-knockout mouse kidneys confirmed elevated apoptosis via GO analysis. Consistently, TUNEL staining showed mice with high K/BW ratio exhibited significant stronger positive signals in the THP+ cyst, while Pkd1/IP1 DKO mice had reduced K/BW ratio and TUNEL signals. Moreover, autophagy markers LC3II/I and Atg12 were decreased in Pkd1 SKO but restored in DKO mice, suggesting autophagy defect in cystogenesis and recovery upon IP1 deletion. Atg5 and Atg7 levels remained unchanged. AlphaFold3 predicted that IP1 contains a functional LC3-interacting region (LIR) domain that interacts with LC3. However, this interaction was not observed in the presence of PC1, suggesting that PC1 may suppress or compete with this binding. These predictions were supported by co-IP experiments in WT and Pkd1-knockout mouse kidneys. IP1 co-precipitated with LC3, however, this interaction was abolished in IP1-knockout mice, indicating that Pkd1 deficiency is required for stabilizing the LC3–IP1 interaction in ADPKD and may contribute to autophagy defect in ADPKD.
Conclusion
Our study provides the first evidence that PC1 may directly regulates the autophagy machinery, and that IP1 deletion may contribute to mitigate cyst progression in ADPKD via reactivating autophagy and suppressing apoptosis. These findings highlight a previously unrecognized role of IP1 in modulating cell death pathways in the kidney and suggest it as a potential therapeutic target for ADPKD.
Funding
- NIDDK Support