Abstract: SA-PO0762
Podocyte-Specific CerS6 Knockout Inhibits C16 Ceramide Production and Attenuates Adriamycin-Induced FSGS
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 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
- Zhao, Qingwei, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Ragi, Nagarjunachary, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Tamayo, Ian M., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Zhang, Shiqi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Saliba, Afaf, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Merscher, Sandra, University of Miami, Coral Gables, Florida, United States
- Fornoni, Alessia, University of Miami, Coral Gables, Florida, United States
- Zhou, Daohong, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Zhang, Guanshi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background
Chronic kidney disease (CKD) impacts millions worldwide and ranks among the leading causes of mortality in the U.S., with focal segmental glomerulosclerosis (FSGS) as a primary glomerular cause. Central to FSGS is podocyte injury and loss, yet the mechanisms driving podocyte vulnerability, particularly in toxin-induced kidney injury such as Adriamycin (ADR)-induced nephropathy, remain elusive. Recent studies suggest that ceramide metabolism, specifically C16 ceramide (Cer) and its synthesizing enzyme, ceramide synthase 6 (CerS6), promotes apoptosis and fibrosis. However, their therapeutic relevance in kidney disease is unexplored. This study investigates the role of podocyte CerS6 and C16 Cer in FSGS progression and assesses the potential protective effects of CerS6 inhibition.
Methods
To explore CerS6's role in kidney function, we developed podocyte-specific CerS6 knockout mice (CerS6KO). CerS6KO and wild-type (WT) littermates received ADR or vehicle (V) treatment. Biweekly urine samples were analyzed for the albumin-to-creatinine ratio (uACR). Blood urea nitrogen (BUN) levels were measured, and kidney tissues were examined via histology and matrix-assisted laser desorption/ionization mass spectrometry imaging for spatial lipidomics.
Results
ADR treatment reduced body and kidney weights in WT mice, with elevated uACR and BUN, which were mitigated in CerS6KO mice. Histology showed pronounced mesangial matrix expansion and collagen deposition in ADR-treated WT mice, which was attenuated in ADR-treated CerS6KO mice. Spatial lipidomics revealed the altered C16 Cer species in the glomeruli of ADR-treated WT mice, which was reversed in ADR-treated CerS6KO mice. Multivariate analysis distinguished lipid profiles among WT+ADR, WT+V, and CerS6KO+ADR groups, with C16 Cer as the top discriminator (highest VIP score), suggesting its potential as an early biomarker for ADR-induced FSGS and the protective role of CerS6 deficiency against podocyte injury.
Conclusion
This study demonstrates that podocyte-specific CerS6 deficiency attenuates ADR-induced FSGS by reducing C16 Cer levels, mitigating podocyte injury, and improving kidney function. C16 Cer emerges as a potential early biomarker for FSGS, and CerS6 inhibition offers a promising therapeutic strategy for FSGS.
Funding
- Other U.S. Government Support