Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice

Abstract

Aim20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-dependent eicosanoids that play opposite roles in the regulation of vascular tone, inflammation, and apoptosis. 20-HETE aggravates, whereas EETs ameliorate ischemia/reperfusion (I/R)-induced organ damage. EETs are rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH). We hypothesized that sEH gene (EPHX2) deletion would increase endogenous EET levels and thereby protect against I/R-induced acute kidney injury (AKI).MethodsKidney damage was evaluated in male wildtype (WT) and sEH-knockout (KO)-mice that underwent 22-min renal ischemia followed by two days of reperfusion. CYP-eicosanoids were analyzed by liquid chromatography tandem mass spectrometry.ResultsContrary to our initial hypothesis, renal function declined more severely in sEH-KO mice as indicated by higher serum creatinine and urea levels. The sEH-KO-mice also featured stronger tubular lesion scores, tubular apoptosis, and inflammatory cell infiltration. Plasma and renal EET/DHET-ratios were higher in sEH-KO than WT mice, thus confirming the expected metabolic consequences of sEH deficiency. However, CYP-eicosanoid profiling also revealed that renal, but not plasma and hepatic, 20-HETE levels were significantly increased in sEH-KO compared to WT mice. In line with this finding, renal expression of Cyp4a12a, the murine 20-HETE-generating CYP-enzyme, was up-regulated both at the mRNA and protein level, and Cyp4a12a immunostaining was more intense in the renal arterioles of sEH-KO compared with WT mice.ConclusionThese results indicate that the potential beneficial effects of reducing EET degradation were obliterated by a thus far unknown mechanism leading to kidney-specific up-regulation of 20-HETE formation in sEH-KO-mice.

Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

“…Unlike the less studied EDPs, EETs have been extensively reported to be antiinflammatory, analgesic, vaso-validative, and cardio-protective (25)(26)(27). EETs were also regarded to be renoprotective in rodent and murine models of I/R-and cisplatincaused AKI (13)(14)(15)28). However, the reno-protective effect of EETs in previous studies was all conjectural based on the pharmacological intervention with either the administration of a sEH inhibitor or the targeted gene disruption of sEH (13)(14)(15)28).…”

Thioredoxin‐Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

“…Renal I/R is one of the major causes of AKI, while cardiovascular surgery and renal transplantation may also cause ischemia AKI in clinical settings [39]. In animal models, the exaggerated vulnerability of the diabetic kidney to the ischemic insult could be attributed to activation of proinflammatory cytokine pathways [40].…”

Chiral lipidomics of monoepoxy and monohydroxy metabolites derived from long-chain polyunsaturated fatty acids

“…All animal experiments were performed in accordance with the guidelines of the Charité University Berlin and approved by local German authorities (LaGeSo, G0146/16, Berlin, Germany). WT and sEH-KO mice were originally established by Boehringer-Ingelheim Pharmaceuticals and were then further backcrossed for nine generations onto C57BL/6ByJ before being used in our studies (17,18). The animals were kept under specific pathogenfree conditions with a standard 12:12 h light-dark cycle and had ad libitum access to water and standard chow.…”