Abstract: FR-PO0782
Senescence-Associated Secretory Phenotype and the Role of Intercellular Adhesion Molecule 1 (ICAM1) Pathway in Aged and Injured Podocytes
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Sharara, Jana, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States
- Pippin, Jeffrey W., University of Washington Division of Nephrology, Seattle, Washington, United States
- Zarouk, Alexander A., Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States
- Tran, Uyen, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States
- Shankland, Stuart J., University of Washington Division of Nephrology, Seattle, Washington, United States
- Wessely, Oliver, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States
Background
Proteinuric glomerular diseases are a leading cause of chronic kidney disease (CKD) and endstage kidney disease (ESKD) with the most common being Focal Segmental Glomerulosclerosis (FSGS). In addition, kidney function progressively declines with age. While it is known that age impacts CKD onset/progression, the underlying molecular mechanisms are less understood. Within the glomerulus, the podocytes, specialized epithelial cells lining the glomerular basement membrane, are the first cell type to be affected by injury and age. These podocytes exhibit morphological changes and functional impairment, which is accompanied by the transcriptional activation of inflammatory and senescence-associated secretory proteins (SASPs). The present study aims to identify the most critical SASPs mediating autocrine podocyte injury and aging.
Methods
To assess the intersection between podocyte injury and aging, we utilized Adriamycin treatment on old mouse podocytes as a nephropathy injury model focusing on apoptosis as the primary readout using a Caspase 3/7 assay. Based on previously published aging-induced SASPs we selected antagonists to thirteen of these signaling pathways and performed a Design-of-Experiment (DoE) approach to identify which antagonist(s) mitigate Adriamycin-induced apoptosis. The findings were validated using a one-factor-at-a-time (OFAT) approach. Injury pathways were further characterized by qRT-PCR and Western analyses.
Results
The DoE analysis identified 3 SASP antagonists (A205804, ML339, Marimastat) that reduced apoptosis in a combinatorial setting. Among those, the ICAM1 inhibitor, A205804, reduced the apoptosis compared to Adriamycin by 30% (p=0.0055). Moreover, qRT-PCR analysis demonstrated that Adriamycin caused stress-induced Cdkn1a-dependent senescence and this resulted in a specific upregulation of Icam1 mRNA and ectopic activation of its signaling pathway
Conclusion
The present study identifies the ICAM1 pathway as an injury-induced signaling cascade in podocytes that promotes apoptosis upon exposure to Adriamycin. With ICAM1 signaling as a mediator of podocyte injury antagonizing this pathway may serve as a potential apoptosis-sparing therapy for podocytopathies.
Funding
- NIDDK Support