Abstract: FR-PO632
Regulated Cell Death in the Pathogenesis of Cystic Kidney Diseases
Session Information
- Cystic Kidney Diseases: Mechanisms and Models
October 25, 2024 | 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: Cystic
Authors
- Kieckhöfer, Emilia, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Ebert, Lena K., Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Benzing, Thomas, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Schermer, Bernhard, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
Group or Team Name
- Nephrolab Cologne.
Background
Hereditary cystic kidney diseases, such as autosomal dominant/recessive polycystic kidney disease (ADPKD/ARPKD) or nephronophthisis (NPH) are caused by mutations in genes encoding proteins essential for the structure and function of primary cilia. Cilia are sensory organelles that project from the surface of tubular epithelial cells into the lumen, functioning like diminutive cellular antennae. In many cystic kidney diseases, a significant loss of tubular epithelial cells occurs. Consequently, we investigated the extent to which pathways of regulated cell death (RCD) are interconnected with cilia and play a role in cystic kidney pathologies.
Methods
We studied pathways of regulated cell death (including apoptosis, necroptosis, and pyroptosis) in cultured renal epithelial cells with and without primary cilia, and in Kif3a-deficient mouse kidneys. Additionally, we deleted Ripk3 and GsdmD in the JCK mouse model of cystic kidney disease and performed renal phenotyping. To gain mechanistic insights, we conducted proteomics and single-nucleus RNA sequencing (snRNA-Seq) analyses.
Results
Loss of cilia in murine kidney epithelial cells led to an increased expression of the key kinase RIPK3 in vitro and in vivo, enhancing the susceptibility of tubular epithelial cells to necroptotic cell death. Notably, RIPK3 deletion in JCK mice resulted in a significant improvement in renal histology and function. Deleting Gasdermin D (GSDMD), an effector of pyroptosis, had a similar effect in this mouse model. Single-nucleus RNA sequencing (snRNA-Seq) analyses provided insight into the mechanisms underlying cyst formation and the beneficial effects of RIPK3 and GSDMD deletion on various cell populations, offering potential new intervention points.
Conclusion
Taken together, our data highlights the significance of RCD in the development of cystic kidney diseases and ciliopathies, suggesting a potential role of RCD as a target for future therapeutic strategies.