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Kidney Week

Abstract: PO2008

Role of ATE1 in Radiation-Induced Nephrotoxicity

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Ahmad, Anis, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States
  • Bader, Cameron, Department of Microbiology and Immunology, Miller School 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
  • Afaghani, Jumana, 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
  • Fornoni, Alessia, Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, Florida, United States
  • Zeidan, Youssef, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, United States
  • Levy, Robert B., Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, United States
  • Marples, Brian, Department of Radiation Oncology, University of Miami, Miller School of Medicine, Miami, Florida, United States

Group or Team Name

  • Radiation Oncology
Background

Arginylation increases actin polymerization and supports cellular morphology. However, the effect of radiation therapy (RT) on arginylation is not known. This study investigated the impact of RT on arginyltransferase 1 (ATE1) and its role in podocyte morphology and kidney function

Methods

Human podocytes were irradiated with 4 Gy, and preceded by rituximab mAb (100 µg/ml) or IgG (100 µg/ml) treatment, 30 min before RT. Additionally, 6-8-week-old C57BL/6 male and female mice were submitted to either (i) 1x14Gy bilateral kidney-only RT (ii) lethal-dose total body irradiation (TBI 10.5Gy) and rescued by strain-donor hematopoietic stem cell transplantation (HSCT) or (iii) left untreated (sham-RT control). Functional, histopathological, and biochemical changes were studied at baseline and 10 weeks post RT

Results

In podocytes, RT (4Gy) produced time-dependent downregulation of ezrin (30%) and ATE1 (50%) and a significant increase in apoptosis at 4h (p=0.001). Rituximab pretreatment protected from ezrin relocalization and ATE1 downregulation, and podocyte apoptosis. In C57BL/6 mice, RT significantly decreased glomerular surface area and increased mesangial expansion scores in 14Gy and TBI animals compared to controls (p<0.01). Similarly, both RT schedules resulted in significant increases in renal fibrosis (p<0.01), serum BUN (p<0.01), and serum creatinine levels (p<0.01). Western blot analysis showed downregulation of ATE1 in the kidney cortex: 67.7±9.6% (14Gy); 69.3±13.3% (TBI) compared to control. Similarly, IHC data showed a decrease in ATE1 expression in glomeruli after 14Gy (50%) and TBI (70%) compared to control. Podocyte number (WT1) in kidney cortex, also decreased significantly after both RT treatments. TEM showed that both RT schedules resulted in significant increases in GBM thickness when compared to control (p<0.001). Foot process width also increased significantly in 14Gy and TBI animals compared to controls (p<0.001)

Conclusion

Our study demonstrates that rituximab pretreatment protects from ATE1 downregulation and confers radioprotective effects in cultured podocytes. ATE1 may be an important therapeutic target for radiation-induced kidney injuries in HSCT patients

Funding

  • Other NIH Support