Abstract: TH-PO0354
Autophagy Activation in Alport Syndrome Is Insufficient to Mitigate Podocyte Lipotoxicity and Mitochondrial Dysfunction
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Njeim, Rachel, University of Miami Miller School of Medicine, Miami, Florida, United States
- Insenga, Arianna, University of Miami Miller School of Medicine, Miami, Florida, United States
- Saadat, Saeida, University of Miami Miller School of Medicine, Miami, Florida, United States
- Gye, Haley, University of Miami Miller School of Medicine, Miami, Florida, United States
- Fontanella, Antonio Miguel, University of Miami Miller School of Medicine, Miami, Florida, United States
- Zevola, Mario, University of Miami Miller School of Medicine, Miami, Florida, United States
- Molina David, Judith T., University of Miami Miller School of Medicine, Miami, Florida, United States
- Ali, Hassan, University of Miami Miller School of Medicine, Miami, Florida, United States
- Burke, George William, University of Miami Miller School of Medicine, Miami, Florida, United States
- Merscher, Sandra, University of Miami Miller School of Medicine, Miami, Florida, United States
- Mitrofanova, Alla, University of Miami Miller School of Medicine, Miami, Florida, United States
- Fornoni, Alessia, University of Miami Miller School of Medicine, Miami, Florida, United States
Background
Autophagy is essential for podocyte homeostasis, yet its role in Alport syndrome (AS) remains poorly defined. We have previously shown that the accumulation of lipid droplets (LDs) in podocytes contributes to the pathogenesis of proteinuric kidney diseases, including AS, suggesting impaired lipophagy. Mitochondrial dysfunction and defective mitophagy have also been implicated in proteinuric kidney diseases. We hypothesized that impaired podocyte autophagy contributes to LD accumulation, mitochondrial dysfunction, and podocyte injury in AS.
Methods
RNA-Seq datasets from patients with AS and chronic kidney disease, immortalized murine podocytes derived from Col4a3+/+ (IMWT) and Col4a3-/- (IMAS) mice, and kidney cortices from Col4a3+/+ and Col4a3-/- mice, a model of progressive glomerular disease, were analyzed for changes in autophagy markers. Lipophagy was assessed by quantifying LD accumulation following treatment with Lalistat, a lysosomal acid lipase (LAL) inhibitor. Mitophagy was evaluated by measuring apoptosis after liensinine treatment. High-content phenotypic profiling was employed in IMWT and IMAS podocytes treated with autophagy inducers, including metformin, rapamycin, and L-690,330.
Results
Transcriptomic analysis revealed altered expression of genes regulating autophagy in AS. Elevated LC3II/I and GATE16 with reduced p62 expression confirmed enhanced autophagy. LAMP2A expression was increased in IMAS podocytes and Col4a3-/- cortices, indicating chaperone-mediated autophagy (CMA) activation. LAL protein expression was elevated, suggesting enhanced lysosomal lipid degradation. Lalistat increased LD accumulation in IMWT but not IMAS podocytes, indicating that excessive LD accumulation surpasses lipophagic capacity in AS. Elevated PINK1 expression and liensinine-induced apoptosis in IMAS podocytes indicated insufficient mitophagy to prevent damaged mitochondria accumulation. High-content profiling demonstrated that autophagy inducers failed to restore an uninjured phenotype in IMAS podocytes.
Conclusion
Collectively, these findings suggest that although the autophagic machinery is enhanced in AS, it remains insufficient to clear excess lipids or dysfunctional mitochondria and fails to prevent podocyte injury.
Funding
- NIDDK Support