Abstract: FR-PO186
Induction of Podocyte-Specific SMPDL3b Mitigates Radiation-Induced Kidney Damage
Session Information
- AKI: Mechanisms
October 25, 2024 | 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
- Mallela, Shamroop Kumar, Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, Florida, United States
- Ansari, Saba, 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
- Merscher, Sandra M., 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, 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
The kidneys' high sensitivity to radiation limits the dose used in radiotherapy (RT) for abdominal and paraspinal tumors, leading to radiation nephropathy (RN). This study investigates the role of the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in renal podocyte response to radiation or cisplatin-induced injury.
Methods
10-14-week-old WT received 4 Gy bilateral kidney irradiation with or without cisplatin (3 mg/kg). 20 weeks post-RT, urine, and serum samples were analyzed for ACR, BUN, and creatinine levels, and glomerular basement membrane (GBM) ultrastructure was assessed via TEM. Another group of mice with podocyte-specific doxycycline-inducible SMPDL3b expression (SMPDL3b transgenic mice (SMP Tg)) kidney received 14 Gy. 20 weeks post-RT, kidney sections were stained with H&E, Periodic Acid-Schiff, and Picro Sirius Red. Kidney cortex samples were analyzed for ceramide-1-phosphate (C1P) levels using mass spectrometry.
Results
20 weeks post-4Gy or cisplatin treatment: i) RT or cisplatin significantly reduced podocyte number and SMPDL3b expression (p < 0.001), with no further change observed with combined treatment; ii) RT or cisplatin significantly increased GBM thickness and foot process width (p < 0.05), which further increased with combined treatment (p = 0.0005 and 0.002); iii) RT or cisplatin significantly increased serum BUN levels (p <0.05), with no further increase observed with combined treatment; iv) RT or cisplatin significantly increased serum creatinine levels (p <0.05), which further increased with combined treatment (p < 0.002); v) RT did not significantly increase urine ACR, while cisplatin did (p = 0.03), but there was no significant difference with combined treatment; vi) RT did not increase C1P levels, but combined treatment did.
20 weeks post-14 Gy irradiation: i) RT significantly decreased podocyte number in WT mice (p = 0.006), but not in SMP Tg mice; ii) RT significantly increased the mesangial expansion score in WT mice, but not in SMP Tg mice; iii) RT did not significantly affect serum BUN, creatinine, urine ACR, and C1P levels in SMP Tg mice.
Conclusion
Induction of SMPDL3b reduces radiation-induced podocyte injury and restores C1P levels, suggesting that SMPDL3b is a potential therapeutic target for mitigating RN.
Funding
- Other NIH Support