title: Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy.
abstract: 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.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Hye Khan
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: Brian
authors.initials: B
authors.lastname: Fish
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: Geneva
authors.initials: G
authors.lastname: Wahl
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, U.S.A.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, U.S.A.
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Paudyal
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: John E
authors.initials: JE
authors.lastname: Moulder
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.affiliation: 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. Eric.Cohen@va.gov.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Cohen
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002216:Captopril / Q000494:pharmacology; D000072467:Cytochrome P450 Family 2; D019610:Cytoprotection; D015777:Eicosanoids / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000378:metabolism; D005355:Fibrosis; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015777:Eicosanoids; D053222:Fas Ligand Protein; C491898:Fas protein, rat; C505662:Faslg protein, rat; D011837:Radiation-Protective Agents; D019014:fas Receptor; D002216:Captopril; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase
keywords: Fas; afferent arteriole; apoptosis; novel small lipid molecule; radiotherapy