Abstract: TH-PO0254
Pharmacologic Inhibition of Ceramide Synthases Ameliorates Adriamycin-Induced Kidney Injury and Suppresses Pathogenic C16 Ceramide Accumulation
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Ding, Yitong, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- 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
- Lee, Naulle, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Montellano, Richard, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 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
Ceramide (Cer) metabolism is dysregulated in chronic kidney disease, with accumulating evidence implicating specific Cer species, particularly C16 Cer, in the progression of renal injury. This study investigated whether pharmacological inhibition of ceramide synthases (CerSs) using fumonisin B1 (FB1) modulates injury-associated lipid remodeling and protects against kidney dysfunction in a mouse model of Adriamycin (ADR)-induced nephropathy.
Methods
Male C57BL/6NJ mice at eight weeks of age (n=6/group) received i.p. injection of ADR at 5 mg/kg, once a week, for 4 consecutive weeks, with or without FB1 (0.01 mg/kg/d in drinking water), a pan-CerS inhibitor. Renal function was assessed by urinary albumin-to-creatinine ratio (uACR) and blood urea nitrogen (BUN). Longitudinal urinary lipidomics was performed with a Thermo Vanquish liquid chromatography system coupled to an Orbitrap mass spectrometer to profile Cer species. Principal component analysis (PCA), heatmap visualization, variable importance in projection (VIP) scores, and two-way repeated-measures ANOVA were used to evaluate temporal changes in Cer metabolism.
Results
ADR treatment significantly impaired renal function with increased uACR and BUN, while co-treatment with FB1 significantly attenuated these functional declines (P<0.0001). PCA revealed progressive divergence of urinary Cer profiles following the ADR treatment, with clearly separated clusters at 2 and 4 weeks from the baseline. Heatmap and longitudinal analyses showed marked accumulation of urinary C16 Cer at 4 weeks post ADR treatment, which was significantly reduced by FB1 treatment (P<0.0001). VIP analysis identified C16 Cer and C24 Cer as the top discriminatory lipids among these different groups of mice (VIP>1). While ADR decreased urinary C24 Cer, FB1 partially restored its levels (P<0.0001). Consequently, the C16/C24 ceramide ratio, a pathogenic lipid signature, was elevated by ADR and normalized by FB1 treatment (P<0.0001).
Conclusion
Pharmacological inhibition of CerSs with FB1 attenuates ADR-induced kidney injury by suppressing pathogenic C16 Cer production, restoring the Cer balance, and improving renal function. These findings identify CerS activity as a promising therapeutic target in kidney disease.
Acknowledgment
This work was funded by the Department of Defense (Grant # HT94252410202).
Funding
- Other U.S. Government Support