Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice.
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ABSTRACT:
SUBMITTER: Klocke J
PROVIDER: S-EPMC6586931 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsAlcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored.MethodsTo decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2fl/fl). Alb-Cre; Ephx2fl/fl and control (Ephx2fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model.ResultsWe observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding.ConclusionsThese findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.
| S-EPMC7851189 | biostudies-literature
Project description:BackgroundPatients with systemic lupus erythematosus (SLE), an autoimmune disease, have a higher risk of cardiovascular (CV) disease and death. In addition, up to 40%-50% of SLE patients develop lupus nephritis (LN) and chronic kidney disease, which is an additional CV risk factor. Thus, the individual contributions of LN and other SLE-specific factors to CV events are unclear.MethodsIn this study, we investigated the effect of LN on the development of CV changes using the female NZBxNZW F1 (NZB/W) mouse model of lupus-like disease, with female NZW mice as controls. Standard serologic, morphologic, immunohistologic, and molecular analyses were performed. In a separate group of NZB/W mice, systolic blood pressure (BP) was measured during the course of the disease using tail plethysmography.ResultsOur data show marked CV changes in NZB/W mice, i.e., increased heart weight, hypertrophy of the left ventricle (LV) and septum, and increased wall thickness of the intramyocardial arteries and the aorta, which correlated with the progression of renal damage, but not with the age of the mice. In addition, systolic BP was increased in NZB/W mice only when kidney damage progressed and proteinuria was present. Pathway analysis based on gene expression data revealed a significant upregulation of the response to interferon beta in NZB/W mice with moderate kidney injury compared with NZB mice. Furthermore, IFI202b and IL-6 mRNA expression is correlated with CV changes. Multiple linear regression analysis demonstrated serum urea as a surrogate marker of kidney function and IFI202b expression as an independent predictor for LV wall thickness. In addition, deposition of complement factors CFD and C3c in hearts from NZB/W mice was seen, which correlated with the severity of kidney disease.ConclusionsThus, we postulate that the pathogenesis of CV disease in SLE is affected by renal impairment, i.e., LN, but it can also be partly influenced by lupus-specific cardiac expression of pro-inflammatory factors and complement deposition.
| S-EPMC10405627 | biostudies-literature
Project description:Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase mediating trimethylation of H3K27, which represses gene expression and is critical to immune regulation. Inhibition of EZH2 is proved to have the potential of treating many diseases. However, whether inhibition of EZH2 affects type I interferon (IFN-I) signaling pathway, the abnormality of which is an important pathogenic mechanism for SLE, is still elusive. Here, we report, unexpectedly, a positive regulatory function of EZH2 in IFN-I signaling pathway, which contributes to the overactivation of IFN-I signaling pathway in SLE. We show that the expression of EZH2 was upregulated and positively correlated with the overexpression of interferon stimulated genes (ISGs) in both peripheral blood mononuclear cells and renal tissues of SLE patients. In vitro inhibition of EZH2 by either siRNAs or chemical inhibitors reduced the phosphorylation of STAT1 and the induction of ISGs stimulated by IFN-I. Additionally, inhibition of EZH2 interfered with the in vivo and ex vivo activation of IFN-I signaling pathway elicited by intravenous injection of adenovirus vector expressing mouse IFN-α5 and exogeneous stimulation with IFN-α, respectively. We evaluated the therapeutic effects of EZH2 inhibitor in NZB/NZW F1 mice which depend on IFN-I signaling pathway for the lupus-like disease development. Administration of EZH2 inhibitor prolonged the survival, reduced the levels of anti-dsDNA autoantibodies, and improved lupus nephritis of the mice. What's more, EZH2 inhibitor attenuated the expression of ISGs in the kidneys of these mice. In summary, we show that excessive EZH2 contributes to the overactivation of IFN-I signaling pathway in SLE. EZH2 inhibitor has the potential to inhibit IFN-I signaling pathway and alleviate lupus nephritis. Additionally, diverse disease driving pathways exist among systemic lupus erythematosus (SLE) patient, and even in the same patients. Common regulators of different pathogenic pathways can be multivalent therapeutic targets. Together with previous studies showing EZH2 is involved in T-cell and B-cell mediated immune responses, EZH2 could be a potent multivalent therapeutic target for SLE.
| S-EPMC8044841 | biostudies-literature
Project description:Soluble epoxide hydrolase (sEH) plays a key role in the metabolic conversion of the protective eicosanoid 14,15-epoxyeicosatrienoic acid to 14,15-dihydroxyeicosatrienoic acid. Accordingly, inhibition of sEH hydrolase activity has been shown to be beneficial in multiple models of cardiovascular diseases, thus identifying sEH as a valuable therapeutic target. Recently, a common human polymorphism (R287Q) was identified that reduces sEH hydrolase activity and is localized to the dimerization interface of the protein, suggesting a relationship between sEH dimerization and activity. To directly test the hypothesis that dimerization is essential for the proper function of sEH, we generated mutations within the sEH protein that would either disrupt or stabilize dimerization. We quantified the dimerization state of each mutant using a split firefly luciferase protein fragment-assisted complementation system. The hydrolase activity of each mutant was determined using a fluorescence-based substrate conversion assay. We found that mutations that disrupted dimerization also eliminated hydrolase enzymatic activity. In contrast, a mutation that stabilized dimerization restored hydrolase activity. Finally, we investigated the kinetics of sEH dimerization and found that the human R287Q polymorphism was metastable and capable of swapping dimer partners faster than the WT enzyme. These results indicate that dimerization is required for sEH hydrolase activity. Disrupting sEH dimerization may therefore serve as a novel therapeutic strategy for reducing sEH hydrolase activity.
| S-EPMC3597810 | biostudies-literature
Project description:A series of N,N'-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane alpha to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 +/- 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.
| S-EPMC2596069 | biostudies-literature
Project description:A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.
| S-EPMC6442743 | biostudies-literature
Project description:Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans-epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including inflammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purified from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i) purified mammalian sEH hydrolyses hepoxilin A? and B? with a V(max) of 0.4-2.5 ?mol/mg/min; ii) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii) hepoxilin hydrolase activity was abolished in liver preparations from sEH(-/-) mice; and iv) liver homogenates of sEH(-/-) mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals. We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrienoic acids. sEH inhibitors might have undesired side effects on hepoxilin signaling.
| S-EPMC3284163 | biostudies-literature
Project description:A soluble epoxide hydrolase (sEH) mediates the metabolism of epoxy fatty acids to form the corresponding vicinal diols, which are usually inactive or less active than the epoxide substrates. The sEH enzyme presents in many organs, including but not limited to the liver, heart, spleen, lung, and kidney. Here we summarized the changes in the expression and activity of sEH in multiple renal diseases, such as acute kidney injury (AKI), diabetic nephrology (DN), chronic kidney diseases (CKD), hypertension-mediated renal damage, and other renal dysfunctions. We also discussed the pharmacologic effects and the underlying mechanisms of sEH inhibition by using an inhibitor of sEH and/or the generic deletion of sEH on multiple renal diseases. We believe that sEH is a potential therapeutic target for renal dysfunction although the target disease needs further investigation.
| S-EPMC6335332 | biostudies-literature
Project description:Mammalian soluble epoxide hydrolase (sEH) converts epoxides to their corresponding diols through the addition of a water molecule. sEH readily hydrolyzes lipid signaling molecules, including the epoxyeicosatrienoic acids (EETs), epoxidized lipids produced from arachidonic acid by the action of cytochrome p450s. Through its metabolism of the EETs and other lipid mediators, sEH contributes to the regulation of vascular tone, nociception, angiogenesis and the inflammatory response. Because of its central physiological role in disease states such as cardiac hypertrophy, diabetes, hypertension, and pain sEH is being investigated as a therapeutic target. This review begins with a brief introduction to sEH protein structure and function. sEH evolution and gene structure are then discussed before human small nucleotide polymorphisms and mammalian gene expression are described in the context of several disease models. The review ends with an overview of studies that have employed the sEH knockout mouse model.
| S-EPMC3733540 | biostudies-literature
Project description:A series of inhibitors of the soluble epoxide hydrolase (sEH) containing two urea groups has been developed. Inhibition potency of the described compounds ranges from 2.0 μM to 0.4 nM. 1,6-(Hexamethylene)bis[(adamant-1-yl)urea] (3b) was found to be a potent slow tight binding inhibitor (IC50=0.5 nM) with a strong binding to sEH (Ki=3.1 nM) and a moderately long residence time on the enzyme (koff=1.05 × 10(-3) s(-1); t1/2=11 min).
| S-EPMC4019751 | biostudies-literature