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

Lee, Jung Pyo; Yang, Seung Hee; Lee, Hee Yoon; Kim, Bora; Cho, Joo Youn; Paik, Jin Ho; Oh, Yun Jung; Lim, Chun Soo; Kim, Yon Su

doi:10.1371/journal.pone.0037075

Cited by 39 publications

(45 citation statements)

References 47 publications

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“…There has been great recent interest in the therapeutic potential of sEH inhibitors as novel antiinflammatories. sEH inhibitors or genetic disruption of sEH in mice reduces inflammation in models of endotoxin-induced pulmonary inflammation (22), ischemia-reperfusion injury (33,34), subarachnoid hemorrhage (35), and the murine ovalbumin model of asthma (36), and in more chronic models including atherogenic diet-induced fatty liver disease and adipose tissue (37) and atherosclerosis (38,39). In contrast, the expression and roles of epoxy-oxylipins during inflammatory resolution have not been investigated.…”

Section: Discussionmentioning

confidence: 99%

CYP450-derived oxylipins mediate inflammatory resolution

Gilroy

Edin

Maeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid-and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1 hi and Ly6c lo monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.oxylipins | resolution | monocyte | phagocytosis | epoxygenase M onocytes and monocyte-derived macrophages play a critical role in chronic inflammation, in part via the production and release of lipid mediators (1). One such lipid precursor, arachidonic acid, is metabolized into families of biologically active mediators by the cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) pathways (2, 3). CYPs metabolize arachidonic acid by: (i) an epoxygenase activity that catalyzes the conversion of arachidonic acid to epoxyeicosatrienoic acids (EETs); (ii) a lipoxygenase-like activity that metabolizes arachidonic acid to midchain hydroxyeicosatetraenoic acids (HETEs); and (iii) ω-and ω-1-hydroxylase activity, which produces ω-terminal HETEs (3). In addition to arachidonic acid, CYPs with epoxygenase activity can also metabolize alternative polyunsaturated fatty acids such as linoleic acid and docosahexaenoic acid into a series of products including epoxyoctadacamonoenoic acids (EpOMEs) and 19,20-epoxydocosapentaenoic acid (EpDPE), respectively, whose functions remain poorly understood (3-5).The main polyunsaturated fatty acid-metabolizing CYPs belong to the CYP2 family, in particular the CYP2J and CYP2C subfamilies (3, 4, 6, 7). Moreover, these CYP-lipid-metabolizing enzymes are the primary sources of eicosanoids in small blood vessels, the kidney, liver, lung, intestines, heart, and pancreas (3, 7). In most organs, EETs and related epoxygenase products are metabolically unstable and are rapidly metabolized. The major pathway that regulates EET metabolism is that catalyzed...

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Section: Discussionmentioning

confidence: 99%

CYP450-derived oxylipins mediate inflammatory resolution

Gilroy

Edin

Maeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

View full text Add to dashboard Cite

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“…Increased DiHOMEs are associated with reduced recovery from ischemia/reperfusion injury in the heart (Edin et al, 2011). In addition, soluble epoxide hydrolase (EPHX2) inhibitors improve recovery from ischemic injury in the kidney, which is associated with increased EpOME to DiHOME ratios (Lee et al, 2012). These toxic effects of LA metabolites may be mediated through induction mitochondrial dysfunction (Moran et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

et al. 2013

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The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics. The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4. We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13). The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js. All four new CYP2J proteins were expressed in Sf21 insect cells. Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives. Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution. CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil). CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes). CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney. CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific. We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues.

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“…Immediately after injury, a subcutaneous osmotic pump (Alzet, Cupertino, CA, USA) was placed closely to the injury site for intrathecal reagent infusion. In the AUDA-treated group, the osmotic pump was filled with 1 mM AUDA (Cayman Chemical, USA) dissolved in 30 % (w/v) solution of hydroxypropyl-β-cyclodextrin (sigma, USA) in 0.9 % sterile saline solution [17], which was microinfused immediately after pump placement at a rate of 0.5 μl/h with the longest infusion time lasting for 7 days. Vehicle animals were only given 30 % (w/v) solution of hydroxypropyl-β-cyclodextrin in 0.9 % sterile saline solution without AUDA in the same volumes as in the AUDA-treated group.…”

Section: Animals and Surgerymentioning

confidence: 99%

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

Chen

Huang

et al. 2015

Mol Neurobiol

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Multiple players are involved in motor and sensory dysfunctions after spinal cord injury (SCI). Therefore, therapeutic approaches targeting these various players in the damage cascade hold considerable promise for the treatment of traumatic spinal cord injury. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). sEH inhibition has been shown to provide neuroprotective effects upon multiple elements of neurovascular unit under cerebral ischemia. However, its role in the pathological process after SCI remains unclear. In this study, we tested the hypothesis that sEH inhibition may have therapeutic effects in preventing secondary damage in rats after traumatic SCI. sEH was widely expressed in spinal cord tissue, mainly confined to astrocytes, and neurons. Administration of sEH inhibitor AUDA significantly suppressed local inflammatory responses as indicated by the reduced microglia activation and IL-1 β expression, as well as the decreased infiltration of neutrophils and T lymphocytes. Meanwhile, reactive astrogliosis was remarkably attenuated. Furthermore, treatment of AUDA improved angiogenesis, inhibited neuron cells apoptosis, alleviated demyelination and formation of cavity and improved motor recovery. Together, these results provide the first in vivo evidence that sEH inhibition could exert multiple targets protective effects after SCI in rats. sEH may thereby serve as a promising multi-mechanism therapeutic target for the treatment of SCI.

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

Cited by 39 publications

References 47 publications

CYP450-derived oxylipins mediate inflammatory resolution

CYP450-derived oxylipins mediate inflammatory resolution

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

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