Kidney Week

Abstract: FR-PO561

Progressive Cellular Senescence Promotes and Senolytic Therapy Delays Cyst Growth in ADPKD

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Mao, Xinyue, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xinyue Mao,

• Li, Lu, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Lu Li,

• Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xia Zhou,

• Harris, Peter C., Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Peter C. Harris,

• Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xiaogang Li,

Background

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited kidney disease. Cellular senescence is permanent proliferative arrest, which accumulates with the progression of a variety of chronic diseases and age in response to endogenous and exogenous stresses. However, the roles and mechanisms of cellular senescence in ADPKD remains elusive.

Methods

To investigate the roles of senescence in ADPKD and evaluate the senescence removal therapy on cyst growth, we treated two Pkd1 mutant mouse models with senescent inducer D-galactose (D-gal) or senolytics. To understand senescence-associated mechanisms in promoting cyst growth, we performed H&E staining, Western blot, qRT-PCR and TUNEL analysis in vitro and in vivo. We also identify SASP produced by Pkd1 mutant cells by mass spectrometry.

Results

Cellular senescence was increased in Pkd1 mutant mouse and human ADPKD kidneys characterized by the increase of the expression of SA-β-Gal and p16. Treatment with senolytics, including dasatinib (D) (7.5mg/kg), quercetin (Q) (75 mg/kg) and D plus Q, delayed cyst growth in kidneys of two Pkd1 mutant mouse models as seen by decrease of cyst index, KW/BW ratios, BUN levels as well as cyst lining epithelial cell proliferation and the release of senescence-associated secretory phenotype (SASP), but increase cystic renal epithelial cell apoptosis. Co-treatment with D plus Q had synergized effect on cyst growth compared to that in kidneys treated with either D or Q alone. The release of SASP from Pkd1 mutant renal epithelial cells stimulated the proliferation of nearby renal epithelial cells and activated renal fibroblasts characterized by the increased the phosphorylation of Akt, S6 and Stat3 and the expression of fibrotic markers (Fibronectin, α-SMA and Col-1). In addition, treatment with senescent inducer, D-gal, promotes cyst growth in Pkd1 mutant kidneys. The clearance of senescence-associated P16^INK4a-positive cells by treating Pkd1^RC/RC:INK-ATTAC and Pkd1^fl/fl:Pkhd1-Cre:INK-ATTAC mice with AP20187 delays the cyst growth in ADPKD.

Conclusion

Senescence was increased in Pkd1 mutant mouse and ADPKD kidneys, which is mediated by p16 associated signaling pathways, and the senescence removal therapy with senolytics is a novel therapeutic strategy for ADPKD treatment.