Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

• Published in: Clinical science (1979) Vol. 130; no. 8; p. 587
• Main Authors: Hye Khan, Md Abdul, Fish, Brian, Wahl, Geneva, Sharma, Amit, Falck, John R, Paudyal, Mahesh P, Moulder, John E, Imig, John D, Cohen, Eric P
• Format: Journal Article
• Language: English
• Published: England 01-04-2016
• Subjects: Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - physiopathology; Acute Kidney Injury - prevention & control; Albuminuria - metabolism; Albuminuria - prevention & control; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Apoptosis - drug effects; Aryl Hydrocarbon Hydroxylases - metabolism; Blood Pressure - drug effects; Blood Urea Nitrogen; Captopril - pharmacology; Cytochrome P450 Family 2; Cytoprotection; Eicosanoids - pharmacology; Fas Ligand Protein - metabolism; fas Receptor - metabolism; Fibrosis; Hypertension - metabolism; Hypertension - physiopathology; Hypertension - prevention & control; Kidney - blood supply; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney - radiation effects; Male; Radiation Injuries, Experimental - metabolism; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - physiopathology; Radiation Injuries, Experimental - prevention & control; Radiation-Protective Agents - pharmacology; Rats; Renal Circulation - drug effects; Signal Transduction - drug effects; Steroid 16-alpha-Hydroxylase - metabolism; radiotherapy; Fas; apoptosis; afferent arteriole; novel small lipid molecule
• ISSN: 1470-8736
• DOI: 10.1042/CS20150778

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.