Soluble Epoxide Hydrolase Activity Determines the Severity of Ischemia-Reperfusion Injury in Kidney

Jung Pyo Lee,Jin Ho Paik,Chun Soo Lim,Yon Su Kim,Hee-Yoon Lee,Joo-Youn Cho,Dong Ki Kim,Bora Kim,Yun Jung Oh,Seung Hee Yang,Leighton R James

doi:10.1371/journal.pone.0037075

Abstract

Soluble epoxide hydrolase (sEH) in endothelial cells determines the plasma concentrations of epoxyeicosatrienoic acids (EETs), which may act as vasoactive agents to control vascular tone. We hypothesized that the regulation of sEH activity may have a therapeutic value in preventing acute kidney injury by controlling the concentration of EETs. In this study, we therefore induced ischemia-reperfusion injury (IRI) in C57BL/6 mice and controlled sEH activity by intraperitoneal administration of the sEH inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA). The deterioration of kidney function induced by IRI was partially moderated and prevented by AUDA treatment. In addition, AUDA treatment significantly attenuated tubular necrosis induced by IRI. Ischemic injury induced the down-regulation of sEH, and AUDA administration had no effect on the expression pattern of sEH induced by IRI. In vivo sEH activity was assessed by measuring the substrate epoxyoctadecenoic acid (EpOME) and its metabolite dihydroxyoctadec-12-enoic acid (DHOME). Ischemic injury had no effects on the plasma concentrations of EpOME and DHOME, but inhibition of sEH by AUDA significantly increased plasma EpOME and the EpOME/DHOME ratio. The protective effect of the sEH inhibitor was achieved by suppression of proinflammatory cytokines and up-regulation of regulatory cytokines. AUDA treatment prevented the intrarenal infiltration of inflammatory cells, but promoted endothelial cell migration and neovascularization. The results of this study suggest that treatment with sEH inhibitors can reduce acute kidney injury.

Highlights

Ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI), which is associated with a high mortality [1,2]
We recently demonstrated a genetic effect of Soluble epoxide hydrolase (sEH) encoded by the EPHX2 gene on the progression of IgA nephropathy [13] and on renal allograft survival [14], and some studies have shown a protective effect of sEH inhibitors against IRI in stroke [15,16] and ischemia-induced myocardial damage [17,18,19]
This study evaluated the effects of the adamantyl alkyl ureabased sEH inhibitor AUDA on renal damage caused by IRI

Summary

Introduction

Ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI), which is associated with a high mortality [1,2]. The pathogenesis of renal IRI has not been fully clarified, hypoxic cell injury both during the ischemic phase and following inflammatory responses in the reperfusion phase are known to play roles [3,4]. Renal EETs are involved in renal blood flow regulation and long-term arterial blood pressure control by acting as an endothelium-derived hyperpolarizing factor on preglomerular vascular smooth muscle cells to dilate the afferent arterioles [8]. Renal and cardiovascular diseases are associated with decreased renal and vascular concentrations of EETs [9]. We recently demonstrated a genetic effect of sEH encoded by the EPHX2 gene on the progression of IgA nephropathy [13] and on renal allograft survival [14], and some studies have shown a protective effect of sEH inhibitors against IRI in stroke [15,16] and ischemia-induced myocardial damage [17,18,19]

Methods

Results

Conclusion