Abstract: TH-PO0596
Extracellular Vesicles Mitigate Glomerular Endothelial Lipid Dysregulation and Mitochondrial Dysfunction in Alport syndrome
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 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
- Sedrakyan, Sargis, Children's Hospital Los Angeles, Los Angeles, California, United States
- Soloyan, Hasmik, Children's Hospital Los Angeles, Los Angeles, California, United States
- Clair, Geremy, Pacific Northwest National Laboratory, Richland, Washington, United States
- Cuala, Janielle M., University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Nelson, Jonathan W., University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Villani, Valentina, Children's Hospital Los Angeles, Los Angeles, California, United States
- Chomoyan, Hripsime, Children's Hospital Los Angeles, Los Angeles, California, United States
- Georgia, Senta K., University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- De Filippo, Roger E., Children's Hospital Los Angeles, Los Angeles, California, United States
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
Background
Alport syndrome (AS) is a hereditary disease caused by mutations in the collagen IV α3, α4, or α5 chains that primarily affects the kidneys, leading to progressive kidney disease. While the genetic basis of AS is well-established, the molecular mechanisms driving disease progression remains incompletely understood. We previously showed that glomerular endothelial cell (GEC) injury precedes podocyte damage, however, the role of GEC dysfunction in driving disease progression remains poorly explored. In this study, we investigate the role of fatty acid synthase (FASN), lipid dysregulation, and mitochondrial dysfunction in GEC injury, and explore the potential of amniotic fluid stem cell (AFSC)-derived extracellular vesicles, (EVs) in restoring glomerular metabolic homeostasis.
Methods
Col4α5-knockout mice were used to study GEC dysfunction at early, mid and late stages of the disease. Metabolic phenotype was assessed by metabolic fluorescent lifetime imaging microscopy (FLIM). GEC from AS and WT mice were compared by bulk RNA-seq, lipidomic and flow analysis in terms of lipid metabolic function. In vitro, the role of human AFSC-EVs to mitigate GEC dysfunction was studied in FASN-silenced primary human GECs. In vivo AS mice were treated with AFSC-EVs and glomeruli were analyzed by sc-RNAseq analysis.
Results
Metabolic changes in AS GEC were marked by mitochondrial depletion and impaired mitochondrial membrane potential. Triglyceride buildup in GECs correlated with glomerular lipid droplet deposition in AS mice. In vitro, FASN silencing impaired mitochondrial function, downregulated key fatty acid metabolism enzymes (ACACA, PGC1a), and induced lipid droplet accumulation. These effects were reversed by AFSC-EVs. Administration of AFSC-EVs normalized the metabolic gene expression profile of GEC in AS mice, highlighting their potential to regulate cellular metabolic functions.
Conclusion
We report for the first time that GEC mitochondrial dysfunction and altered lipid metabolism are defining features of early disease progression in AS and that AFSC-derived EVs can mitigate this pathological phenotype. A deeper understanding of the role of GEC in AS pathobiology may facilitate the development of targeted new therapies.
Funding
- NIDDK Support