Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP-epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analog, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared to non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared to control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen compared to control, and EET-A or captopril decreased BUN by 40–60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60–90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50–90%. Renal interstitial fibrosis, tubular, and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which EET-A or captopril mitigated. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on p53/Fas/FasL apoptotic pathway. Overall, this study demonstrates a novel EET-analog based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

Overall, these findings demonstrate kidney and heart protective effects of AZL-M in SHROB, and these effects were associated with its ability to lower blood pressure and improve endothelial function.

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Arachidonic acid metabolites epoxyeicosatrienoic acids (EETs) protect the kidney in different pathologies. This study investigated the ability of a novel EET analog, EET‐A to mitigate experimental radiation nephropathy caused by total body irradiation (TBI, 11 Gy). Four groups of rats, normal male WAG/RijCmcr rats, TBI rats treated with vehicle (TBI‐V), EET‐A (10mg/kg/d p.o.) treated TBI rats (TBI‐EET‐A), and Captopril (30mg/kg/d p.o.) treated TBI rats (TBI‐Cap) were studied. Kidney damage was assessed from blood urea nitrogen (BUN), albuminuria, nephrinuria, and histopathological changes 12 weeks post TBI. The TBI‐V group had a 3‐fold increase in BUN level compared to control (158±14 vs 50±3 mg/dL). BUN level was lower in TBI‐EET‐A (85±6 mg/dL) and TBI‐Cap (52±2 mg/dL) compared to TBI‐V group. Albumin/creatinine ratio increased 94‐fold in TBI‐V group compared to control (6451±800 vs 20±5 μg/mg), and was reduced in TBI‐EET‐A (1652±382 μg/mg) and TBI‐Cap (103±28 μg/mg) groups. Nephrinuria increased 30‐fold in the TBI‐V compared to control group (15390±1897 vs 48±9 μg/d), and EET‐A (7071±2122) and captopril (222±107) decreased it. Moreover, renal tubular and glomerular injury was reduced in TBI‐EET‐A and TBI‐Cap groups compared to TBI‐V group. These data demonstrate that a novel EET‐analog, EET‐A reduces kidney injury in experimental radiation nephropathy caused by TBI.