Abstract: SA-PO0153
SMPDL3b Induction Preserves Kidney Function and Lipid Homeostasis Following Radiation and Cisplatin Treatment
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ahmad, Anis, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Alnukhali, Mohammed, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Ahmad, Nayab, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Ansari, Saba, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Merscher, Sandra, Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, Florida, United States
- Zeidan, Youssef, Dept of Radiation Oncology, Lynn Cancer Institute, Baptist Health South Florida, Boca Raton, United States
- Pollack, Alan, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Fornoni, Alessia, Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, Florida, United States
- Marples, Brian, Department of Radiation Oncology, University of Rochester, Rochester, New York, United States
Background
Cancer survivors treated with radiation and cisplatin often develop chronic kidney injury, yet the mechanisms remain unclear. Podocytes are particularly vulnerable to cytotoxic stress. SMPDL3b, a lipid-modifying enzyme enriched in podocytes, may protect against renal injury by preserving structure and regulating ceramide–1–phosphate–mediated inflammation and fibrosis.
Methods
8-10-week-old male and female C57BL/6 wild-type (WT) and doxycycline-inducible podocyte-specific SMPDL3B transgenic (SMP TG) mice were treated with 14 Gy kidney radiation (RT), 3 mg/kg cisplatin (CP), or both (RT+CP). Mice were euthanized 20 weeks later. Kidney injury and fibrosis were evaluated by H&E and Picrosirius red staining. Renal function was assessed via serum BUN, creatinine, and urine ACR. Lipidomic analysis of the kidney cortex was performed to quantify ceramide-1-phosphate (C1P) levels and species.
Results
WT mice exposed to RT and/or CP showed significant histological damage, including tubular necrosis, dilated tubules, interstitial fibrosis, and proteinaceous casts. Injury was most severe in the RT+CP group (renal injury score: p < 0.01 vs. NT), with significant glomerular and tubular injury and increased Picrosirius red-positive fibrotic area (p < 0.01). In contrast, SMP TG mice exhibited markedly reduced renal damage after RT (p = 0.03) and RT+CP (p = 0.04), with preservation of tubular architecture and reduced fibrosis.
Renal function was significantly improved in SMP TG mice. Compared to WT-RT and WT-RT+CP mice, SMP TG mice showed reduced serum BUN (p = 0.03), lower serum creatinine (p = 0.04), and significantly improved urine ACR (p = 0.02), suggesting preserved glomerular filtration.
Lipidomic analysis revealed elevated levels of total C1P and pro-inflammatory C1P species in WT mice treated with RT±CP (p < 0.01 vs. NT). These elevations were significantly attenuated in SMP TG mice (p < 0.05), indicating SMPDL3B’s role in modulating stress-induced lipid dysregulation.
Conclusion
SMPDL3B induction in podocytes protects against radiation and cisplatin-induced kidney injury by preserving renal structure, improving function, and normalizing C1P levels. Targeting SMPDL3B offers a promising strategy to prevent chronic nephrotoxicity in cancer survivors.
Funding
- Other NIH Support