Abstract: FR-PO0687
Cellular Senescence Is Associated with Disease Progression in ADPKD
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
- Kenter, Annegien, Erasmus MC, Rotterdam, ZH, Netherlands
- Maryam, Sidrah, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Peters, Dorien J.M., Leids Universitair Medisch Centrum, Leiden, ZH, Netherlands
- Kramann, Rafael, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Hayat, Sikander, Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, NRW, Germany
- Hoorn, Ewout J., Erasmus MC, Rotterdam, ZH, Netherlands
Background
Cellular senescence aids in acute injury repair, but prolonged senescence drives chronic damage. This study investigates whether senescence plays a role in cyst growth and disease progression in autosomal dominant polycystic kidney disease (ADPKD).
Methods
Cellular senescence was analyzed in human ADPKD and healthy kidney tissue using histological staining and single-cell RNA sequencing. ADPKD cyst fluid was analyzed for the senescence-associated secretory profile (SASP). Cyst fluid and individual SASP factors were tested in vitro for their proliferative potential. ADPKD mouse models were used to examine senescence marker expression during disease progression. To assess senescence in patients with ADPKD, we compared the senescence profile in urinary extracellular vesicles (EVs) isolated from patients with stable disease or rapid disease progression.
Results
Compared to healthy human kidney tissue, human ADPKD kidneys showed reduced Lamin B1 and HMGB1 and increased p16 and c-Myc expression, indicating cellular senescence. Although total p21 expression level was not increased in bulk RNA sequencing, the number of p21+ cells detected with single cells sequencing was significantly higher. p16+ and p21+ senescent cells exhibited distinct gene expression profiles, including differences in SASP factors, and originated from different cell types. In cyst fluid from ADPKD patients, we detected several SASP factors. The addition of cyst fluid or individual SASP factors (IL-6, IL-8) promoted cell proliferation in a proximal tubule cell line. In ADPKD mice, increasing disease severity was associated with a loss of Lamin B1 and HMGB1, and increase in p16 levels. Next, we induced senescence in a proximal tubule cell line and conducted proteomic analysis on isolated EVs to establish a senescence-associated EV protein profile. We then used this profile to compare senescence-related proteins in urinary EVs from patients with either stable or progressive ADPKD. This analysis revealed a significant increase in proteins BAX, NRAS, PRMT5, MMP-2 in uEVs of patients with rapid disease progression.
Conclusion
Our findings identify cellular senescence as a hallmark of ADPKD and show that it is associated with disease progression. Accumulation of senescent cells may drive cyst growth and accelerate kidney injury through SASP- and EV-mediated communication.