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Abstract: TH-PO967

Mitigation of Radiation Injury by Epoxyeicosatrienoic Acid Mimetic Assessed by Urinary Proteomics

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Kolbach-Mandel, Ann M., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Cohen, Eric P., University of Maryland, Baltimore, Maryland, United States
  • Mandel, Neil S., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Imig, John D., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Khan, Abdul Hye, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Fish, Brian L., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Kane, Maureen A., University of Maryland, Baltimore, Maryland, United States
  • Huang, Weiliang, University of Maryland, Baltimore, Maryland, United States
Background

Radiation exposure due to radionuclide cancer therapy, accident, or radio-nuclear attack could cause radiation induced nephropathy. Non-biased urinary proteomic analysis can identify novel urine biomarkers that precede tissue injury and may be mechanistically relevant.

Methods

20 male WAG/RijCmcr rats underwent partial body irradiation (PBI) with one leg shielded to allow bone marrow reconstitution. 24 hour urine was collected four weeks after PBI from control (0 Gy) or irradiated (11 Gy) without or with epoxyeicosatrienoic acid (EET) mimetic therapy. Renal injury was assessed by urine protein and urine creatinine. Proteomic analysis was performed on urine (ultrafiltered > 3kDa) using standardized methods. Protein abundance determinations (% Extracted Ion Chromatograph, % XIC) were normalized to total urine protein, urine creatinine, and rat weight. Final protein concentrations are reported as protein/creatinine/weight (mg/g/kg).

Results

Baseline rat weights did not differ according to experimental group. At 4 weeks after PBI the 11 Gy rats weighed significantly less than controls. The radiated rats did not differ in total urine protein, urine creatinine, urine protein/creatinine, or urine volume. Proteinuria occurs starting at six weeks in this model. Mass spectrometry-based proteomics yielded 781 proteins with 99.9% overlap in all experimental groups. The increased abundance of proteins in irradiated rats were largely of extracellular origin and part of biological networks related to nucleic acid, carbohydrate, and collagen metabolism. The EET mimetic significantly changed select proteins related to these networks. Notable changes in mg/creat/body weight were: Malate dehydrogenase 0.06/0.18/0.11, Glyceraldehyde 3 phosphate dehydrogenase 0.05/0.20/0.12, and Lysyl Oxidase 0.01/0.25/0.01.

Conclusion

Radiation exposure results in significant increases in urinary proteins, largely extracellular in origin, related to nucleic acid, carbohydrate, and collagen metabolism. The largest effect was on lysyl oxidase, an enzyme that increases collagen crosslinking which may presage tissue fibrosis in this model.This offers some insight into the known therapeutic benefits of the EET mimetic.

Funding

  • Veterans Affairs Support