scholarly journals Genetic disruption of soluble epoxide hydrolase is protective against streptozotocin-induced diabetic nephropathy

2012 ◽  
Vol 303 (5) ◽  
pp. E563-E575 ◽  
Author(s):  
Guangzhi Chen ◽  
Renfan Xu ◽  
Yinna Wang ◽  
Peihua Wang ◽  
Gang Zhao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Diabetic Mice ◽  
Ampk Signaling ◽  
Beneficial Role ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Gene Inhibition

Cytochrome P-450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important roles in regulating cardiovascular functions. The anti-inflammatory, antiapoptotic, proangiogenic, and antihypertensive properties of EETs suggest a beneficial role for EETs in diabetic nephropathy. Endogenous EET levels are maintained by a balance between synthesis by CYP epoxygenases and hydrolysis by epoxide hydrolases into physiologically less active dihydroxyeicosatrienoic acids. Genetic disruption of soluble epoxide hydrolase (sEH/EPHX2) results in increased EET levels through decreased hydrolysis. This study investigated the effects of sEH gene disruption on diabetic nephropathy in streptozotocin-induced diabetic mice. Streptozotocin-induced diabetic manifestations were attenuated in sEH-deficient mice relative to wild-type controls, with significantly decreased levels of Hb A1c, creatinine, and blood urea nitrogen and urinary microalbumin excretion. The sEH-deficient diabetic mice also had decreased renal tubular apoptosis that coincided with increased levels of antiapoptotic Bcl-2 and Bcl-xl, and decreased levels of the proapoptotic Bax. These effects were associated with activation of the PI3K-Akt-NOS3 and AMPK signaling cascades. sEH gene inhibition and exogenous EETs significantly protected HK-2 cells from TNFα-induced apoptosis in vitro. These findings highlight the beneficial role of the CYP epoxygenase-EETs-sEH system in the pathogenesis of diabetic nephropathy and suggest that the sEH inhibitors available may be potential therapeutic agents for this condition.

Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

2020 ◽  
Vol 209 (4-6) ◽  
pp. 177-188
Author(s):  
Katerina Cizkova ◽  
Katerina Koubova ◽  
Tereza Foltynkova ◽  
Jana Jiravova ◽  
Zdenek Tauber
Keyword(s):  
Cell Differentiation ◽  
Colorectal Carcinoma ◽  
Cell Lines ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Intestinal Cell ◽  
Caco2 Cells ◽  
Important Player ◽  
Ht 29

There is growing evidence that soluble epoxide hydrolase (sEH) may play a role in cell differentiation. sEH metabolizes biologically highly active and generally cytoprotective epoxyeicosatrienoic acids (EETs), generated from arachidonic acid metabolism by CYP epoxygenases (CYP2C and CYP2J subfamilies), to less active corresponding diols. We investigated the effect of sEH inhibitor (TPPU) on the expression of villin, CYP2C8, CYP2C9, CYP2J2, and sEH in undifferentiated and in vitro differentiated HT-29 and Caco2 cell lines. The administration of 10 μM TPPU on differentiated HT-29 and Caco2 cells resulted in a significant decrease in expression of villin, a marker for intestinal cell differentiation. It was accompanied by a disruption of the brush border when microvilli appeared sparse and short in atomic force microscope scans of HT-29 cells. Although inhibition of sEH in differentiated HT-29 and Caco2 cells led to an increase in sEH expression in both cell lines, this treatment had an opposite effect on CYP2J2 expression in HT-29 and Caco2 cells. In addition, tissue samples of colorectal carcinoma and adjacent normal tissues from 45 patients were immunostained for sEH and villin. We detected a significant decrease in the expression of both proteins in colorectal carcinoma in comparison to adjacent normal tissue, and the decrease in both sEH and villin expression revealed a moderate positive association. Taken together, our results showed that sEH is an important player in intestinal cell differentiation.

scholarly journals IN VITRO SOLUBLE EPOXIDE HYDROLASE ENZYME INHIBITORY ACTIVITY OF SOME NOVEL CHALCONE DERIVATIVES

2012 ◽  
Vol 2 (4) ◽  
Author(s):  
Kuppusamy Asokkumar ◽  
Lokeswari Prathyusha Tangella ◽  
Muthusamy Umamaheshwari ◽  
Thirumalaisamy Shivashanmugam ◽  
Varadharajan Subhadradevi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Chalcone Derivatives

In vitro and in silico investigation of anthocyanin derivatives as soluble epoxide hydrolase inhibitors

2018 ◽  
Vol 112 ◽  
pp. 961-967 ◽  
Author(s):  
Jang Hoon Kim ◽  
In Sook Cho ◽  
Jaihyuk Ryu ◽  
Ji Sun Lee ◽  
Jong Seong Kang ◽  
...  
Keyword(s):  
In Silico ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase Inhibitors

Soluble Epoxide Hydrolase Deletion Attenuated Nicotine-induced Arterial Stiffness via Limiting the Loss of SIRT1

2021 ◽  
Author(s):  
Shuiqing Hu ◽  
Jinlan Luo ◽  
Menglu Fu ◽  
Liman Luo ◽  
Yueting Cai ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Vascular Remodeling ◽  
Epoxide Hydrolase ◽  
Vascular Dysfunction ◽  
Soluble Epoxide Hydrolase ◽  
Protective Effects ◽  
Nicotine Treatment ◽  
Beneficial Effects ◽  
Sirt1 Inhibitor

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide (NAM, SIRT1 inhibitor) simultaneously for four weeks. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2-/- mice without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced MMP2 upregulation via SIRT1-mediated YAP deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.

scholarly journals Deficiency of C3a receptor attenuates the development of diabetic nephropathy

2019 ◽  
Vol 7 (1) ◽  
pp. e000817 ◽  
Author(s):  
Xiao-Qian Li ◽  
Dong-Yuan Chang ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Diabetic Nephropathy ◽  
T Cell ◽  
Adaptive Immunity ◽  
Renal Damage ◽  
Inflammatory Responses ◽  
Gene Knockout ◽  
Diabetic Mice ◽  
Pathogenic Role

ObjectiveDiabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN.Research design and methodsThe expression of C3aR was examined in the renal specimen of patients with DN. Using a C3aR gene knockout mice (C3aR−/−), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a.ResultsCompared with normal controls, the renal expression of C3aR was significantly increased in patients with DN. C3aR−/− diabetic mice developed less severe diabetic renal damage compared with wild-type (WT) diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T-cell adaptive immunity in C3aR−/− diabetic mice compared with WT diabetic mice, and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophage infiltration. In vitro study demonstrated C3a can enhance macrophage-secreted cytokines which could induce inflammatory responses and differentiation of T-cell lineage.ConclusionsC3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T-cell adaptive immunity, possibly by influencing macrophage-secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.

scholarly journals Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling

2010 ◽  
Vol 298 (2) ◽  
pp. H679-H687 ◽  
Author(s):  
Matthias J. Merkel ◽  
Lijuan Liu ◽  
Zhiping Cao ◽  
William Packwood ◽  
Jennifer Young ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Glucose Deprivation ◽  
Soluble Epoxide Hydrolase ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Mutant Proteins ◽  
Stat3 Signaling ◽  
Stat3 Inhibition

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.

Suppressions of chronic glomerular injuries and TGF-β1 production by HGF in attenuation of murine diabetic nephropathy

2004 ◽  
Vol 286 (1) ◽  
pp. F134-F143 ◽  
Author(s):  
Shinya Mizuno ◽  
Toshikazu Nakamura
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Renal Dysfunction ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Renal Diseases ◽  
Glomerular Mesangial Cells ◽  
Diabetic Mice

Diabetic nephropathy is now the leading cause of end-stage renal diseases, and glomerular sclerotic injury is an initial event that provokes renal dysfunction during processes of diabetes-linked kidney disease. Growing evidence shows that transforming growth factor-β1 (TGF-β1) plays a key role in this process, especially in eliciting hypertrophy and matrix overaccumulation. Thus it is important to find a ligand system to antagonize the TGF-β1-mediated pathogenesis under high-glucose conditions. Herein, we provide evidence that hepatocyte growth factor (HGF) targets mesangial cells, suppresses TGF-β1 production, and minimizes glomerular sclerotic changes, using streptozotocin-induced diabetic mice. In our murine model, glomerular sclerogenesis (such as tuft area expansion and collagen deposition) progressed between 6 and 10 wk after the induction of hyperglycemia, during a natural course of diabetic disease. Glomerular HGF expression levels in the diabetic kidney transiently increased but then declined below a basal level, with manifestation of glomerular sclerogenesis. When anti-HGF IgG was injected into mice for 2 wk (i.e., from weeks 4 to 6 after onset of hyperglycemia), these glomerular changes were significantly aggravated. When recombinant HGF was injected into the mice for 4 wk (i.e., between 6 and 10 wk following streptozotocin treatment), the progression of glomerular hypertrophy and sclerosis was almost completely inhibited, even though glucose levels remained unchanged (>500 mg/dl). Even more important, HGF repressed TGF-β1 production in glomerular mesangial cells even under hyperglycemic conditions both in vitro and in vivo. Consequently, not only albuminuria but also tubulointerstitial fibrogenesis were attenuated by HGF. Overall, HGF therapy inhibited the onset of renal dysfunction in the diabetic mice. On the basis of these findings, we wish to emphasize that HGF plays physiological and therapeutic roles in blocking renal fibrogenesis during a course of diabetic nephropathy.

scholarly journals Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiayi Wan ◽  
Mingyang Hu ◽  
Ziming Jiang ◽  
Dongwei Liu ◽  
Shaokang Pan ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial Cells ◽  
High Resolution Mass Spectrometry ◽  
Microvascular Complications ◽  
Lysine Acetylation ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.

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