0377 : Soluble epoxide hydrolase inhibition reduces the cardiovascular consequences of renal ischemia-reperfusion

Abstract

Ischemia-reperfusion (I/R) injury is an immediate complication of renal transplantation and a determinant of persistent allograft injury and related cardiovascular outcomes. Epoxyeicosatrienoic acids (EETs) are endothelium- derived hyperpolarizing factors with anti-inflammatory and vasodilator properties. The objective of our study was to evaluate the effects of t-AUCB, a pharmacological inhibitor of EETs degradation, on the shortand potential long-term consequences of renal I/R. C57Bl/6J mice were subjected to 30-min renal bilateral I/R, and subsequently received t-AUCB (15 mg/l PO) or vehicle. Kidney function and pathology were evaluated after 48 hours (h48), 28 days (d28) and 8 months (m8). Vascular function on isolated renal artery, and cardiac function were evaluated at d28 (echocardiography, invasive hemodynamics), and m8(echocardiography). Renal I/R produced severe renal failure at h48, and mild renal failure at d28 and m8, non significantly reduced by t-AUCB (plasma creatinine sham 5.0±1.7 μmol/l; d28 I/R 14.9±2.7; d28 I/R+t-AUCB 10.8±1.1; m8 I/R 6.6±1.2; m8 I/R+t-AUCB 7.0±1.3). Kidney histology revealed severe tubulointerstitial lesions at d28, reduced by t-AUCB (sham 0.3±0.1; I/R 1.5±0.2, p<0.05 vs sham; I/R+t-AUCB 1.2±0.2, p<0.05 vs I/R), which had recovered at m8. Cardiac echocardiography showed that t-AUCB reduced I/R-induced systolic and diastolic dysfunction (LV fractional shortening: sham 45±1%; I/R 40±1%, p<0.05 vs sham; I/R+t-AUCB 43±1%, p<0.05 vs I/R) and diastolic dysfunction (E/A: sham 1.2±0.1; I/R 1.6±0.1, p<0.05 vs sham; I/R+t-AUCB 1.3±0.1, p<0.05 vs I/R). Impaired relaxation of the renal artery to acetylcholine was present in I/R mice, significantly reduced by t-AUCB. Our results suggest that increasing EETs bioavailability is a promising approach to reduce the consequences of renal I/R on the kidney and cardiovascular dysfunction associated with renal failure. The author hereby declares no conflict of interest