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 analogue, 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 with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with 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 was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.
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Radiation nephropathy is mitigated by EET-A and also by captopril. The severe histological injury of radiation nephropathy includes cast formation and mesangiolysis. Both are significantly attenuated by EET-A or captopril. PAS stained kidney, 200x magnification. For further details see pp. 587–599. Image kindly provided by Dr. Md Abdul Hye Khan.Close Modal
Research Article|
March 08 2016
Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy
Md. Abdul Hye Khan;
Md. Abdul Hye Khan
*Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Brian Fish;
Brian Fish
†Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Geneva Wahl;
Geneva Wahl
*Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Amit Sharma;
Amit Sharma
*Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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John R. Falck;
John R. Falck
‡Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, U.S.A.
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Mahesh P. Paudyal;
Mahesh P. Paudyal
‡Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, U.S.A.
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John E. Moulder;
John E. Moulder
†Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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John D. Imig;
John D. Imig
*Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Eric P. Cohen
†Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
§Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
Correspondence: Eric P. Cohen (e-mail Eric.Cohen@va.gov).
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Clin Sci (Lond) (2016) 130 (8): 587–599.
Article history
Received:
October 30 2015
Revision Received:
January 14 2016
Accepted:
January 15 2016
Accepted Manuscript online:
January 15 2016
Citation
Md. Abdul Hye Khan, Brian Fish, Geneva Wahl, Amit Sharma, John R. Falck, Mahesh P. Paudyal, John E. Moulder, John D. Imig, Eric P. Cohen; Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. Clin Sci (Lond) 1 April 2016; 130 (8): 587–599. doi: https://doi.org/10.1042/CS20150778
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