Abstract: FR-PO0658
Klotho Attenuates ADPKD Progression by Epigenetic Reprogramming and Multimodal Suppression of Cystogenic Pathways
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
- Lyu, Jiayi, Shanghai Changzheng Hospital, Shanghai, China
- Xue, Cheng, Shanghai Changzheng Hospital, Shanghai, China
- Mei, Changlin, Shanghai Changzheng Hospital, Shanghai, China
- Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary nephropathy caused by PKD1 or PKD2 mutations, often progressing to end-stage kidney disease (ESKD). Klotho, a renoprotective protein with anti-aging functions, has emerged as a potential modulator of disease progression, though its mechanistic role in ADPKD remains unclear.
Methods
We investigated Klotho expression in Pkd1-deficient cell lines, ADPKD mouse models, and human kidney tissues. Functional assays assessed the effects of recombinant Klotho on proliferation, fibrosis, ferroptosis, and inflammation. DNA methylation profiling, chromatin immunoprecipitation (ChIP), and DNMT1 inhibition explored the epigenetic regulation of Klotho.
Results
Klotho expression was significantly reduced in ADPKD, associated with DNMT1-mediated hypermethylation of the Klotho promoter. Exogenous Klotho treatment delayed disease progression. Mechanistically, Klotho inhibited key cystogenic signaling pathways, including PI3K-AKT, JAK2-STAT3, and NF-κB. It also attenuated ferroptosis via upregulation of GPX-4 and reduced TGF-β-mediated fibrosis.
Conclusion
This study identifies Klotho as a critical suppressor of ADPKD progression through epigenetic and signaling modulation. Targeting the DNMT1-Klotho axis offers a promising therapeutic approach for halting cyst growth, inflammation, and fibrosis in ADPKD.