Epoxyeicosatrienoic Acid Analog Reduces Proteinuria And Renal Cast Formation In Experimental Radiation Nephropathy
Authors: Benson Stacey , Fish Brian , Khan Md. Abdul Hye , Sharma Amit , Cohen Eric P. , Falck John R. , Imig John D. 
Published: November 2023

Thirty‐three million Americans are estimated to have chronic kidney disease (CKD). Exposure to radiation through industrial accidents, terrorist events, or total body irradiation (TBI) associated with hematopoietic stem cell transplant (HSCT), increases the risk for acquiring CKD. Clinical symptoms of human radiation nephropathy (i.e. azotemia, hypertension, proteinuria, anemia) can present within 6–12 months following irradiation in cases of acute radiation exposure. Current therapies for radiation nephropathy are limited and variable in their success. Our laboratory has demonstrated that epoxygenase metabolites of arachidonic acids epoxyeicosatrienoic acids (EETs) protect the kidney in different pathologies. We have developed novel small molecule EET analogs that protect from cisplatin‐induced and hypertension‐induced kidney injury. The aim of this research study is to examine the efficacy of a novel therapeutic, EET‐A, in reducing kidney damage following total body TBI (11 Gy) in WAG/RijCmcr rats. We also examined the efficacy of the current therapy, captopril (an ACE inhibitor) to treat experimental radiation nephropathy when administered alone or in combination with EET‐A. Four groups (n=6/group) of male WAG/RijCmr rats received TBI and were treated with vehicle (TBI‐V), EET‐A (10mg/kg/d p.o.; TBI‐EET‐A), captopril (15mg/kg/d p.o.; TBI‐Cap), or the combination of captopril and EET‐A (TBI‐Cap, 15mg/kg/d + EET‐A, 10mg/kg/d). Treatment was started when the rats developed azotemia (BUN 30–50 mg/dL) and was continued for 45 days. Renal tissue and urine samples were collected from the rats at the end of the treatment period. Treatments were simultaneously compared in their effectiveness of reducing the effects of radiation nephropathy‐associated proteinuria in rats through analyses of protein‐to‐creatinine ratios, and percent quantification of protein casts within medulla and cortex histological cross‐sections. TBI‐V rats were markedly proteinuric with protein‐creatinine ratio of 59±6 mg/mg. All treatments reduced proteinuria by 20–55% and a one‐way ANOVA demonstrated that overall differences in the protein/creatinine ratio existed between drug treatments, F (5,38)=8.126; p<0.05. Pairwise comparisons between the TBI‐Cap (32.5±5 mg/mg) and TBI‐Cap+EET‐A (30.1±3 mg/mg) revealed no statistical difference (p>0.05). All treatments reduced protenaceous tubular cast formation in TBI rats. TBI‐EET‐A, TBI‐Cap, and TBI‐Cap+EET‐A groups demonstrated a comparable effect in reducing cortical tubular cast formation with ~75% reduction. On the other hand, TBI‐Cap (70%) and TBI‐Cap+EET‐A (86%) treatments were more effective than TBI‐EET‐A (50%) in reducing medullary protein casts. Overall, captopril and its combination with EET‐A were comparatively more effective than EET‐A alone in reducing medullary cast formation. Our data demonstrates that EET‐A or EET‐A in combination with captopril can be effective treatments for radiation nephropathy.