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.
Subject(s)
Acute Kidney Injury/prevention & control , Eicosanoids/pharmacology , Kidney/drug effects , Kidney/radiation effects , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/pharmacology , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , 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 , Fas Ligand Protein/metabolism , Fibrosis , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/prevention & control , Kidney/blood supply , Kidney/metabolism , Kidney/pathology , Male , Radiation Injuries, Experimental/metabolism , Radiation Injuries, Experimental/pathology , Radiation Injuries, Experimental/physiopathology , Rats , Renal Circulation/drug effects , Signal Transduction/drug effects , Steroid 16-alpha-Hydroxylase/metabolism , fas Receptor/metabolismABSTRACT
PURPOSE: Angiotensin II type 1 receptor blockers (ARBs) are widely used in treating hypertension. In the present study, we tested the hypothesis that a novel ARB, azilsartan medoxomil (AZL-M) will prevent renal and cardiovascular injury in the spontaneously hypertensive obese rat (SHROB), a model of cardiometabolic syndrome. METHODS: Male SHROB were treated with vehicle or AZL-M orally for 56 days. Vehicle treated normotensive Wistar-Kyoto (WKY) rats served as controls. The effects of AZL-M on kidney injury, vascular endothelial and heart functions, lipid profile, and glucose tolerance were assessed. RESULTS: AZL-M demonstrated anti-hypertensive effects along with markedly improved vascular endothelial function in SHROB. In these rats, AZL-M demonstrates strong kidney protective effects with lower albuminuria and nephrinuria along with reduced tubular cast formation and glomerular injury. AZL-M treatment also improved left ventricular heart function, attenuated development of left ventricular hypertrophy, and reduced cardiac fibrosis in SHROB. CONCLUSION: 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.
