scholarly journals Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy

2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Xu-shun Jiang ◽  
Xing-yang Xiang ◽  
Xue-mei Chen ◽  
Jun-ling He ◽  
Ting Liu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Autophagic Flux ◽  
Renal Tubular

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.

scholarly journals Genetic Deletion of Soluble Epoxide Hydrolase Attenuates Inflammation and Fibrosis in Experimental Obstructive Nephropathy

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Chin-Wei Chiang ◽  
Hsueh-Te Lee ◽  
Der-Cherng Tarng ◽  
Ko-Lin Kuo ◽  
Li-Ching Cheng ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Interleukin 1 ◽  
Kidney Injury ◽  
Soluble Epoxide Hydrolase ◽  
Obstructive Nephropathy ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Renal Tubular

Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) andsEHdeficient (sEH−/−) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated insEH−/−mice with the exception of glomerulosclerosis. Moreover,sEH−/−mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1β(IL-1β), IL-6, inducible nitric oxide synthase, collagen 1A1, andα-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys ofsEH−/−mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases.

scholarly journals Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates Diet-induced Endoplasmic Reticulum Stress in Liver and Adipose Tissue

2013 ◽  
Vol 288 (20) ◽  
pp. 14189-14199 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Naoto Nagata ◽  
Daniel AbouBechara ◽  
Samah Chahed ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Pharmacological Inhibition

Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity.

scholarly journals Expression of soluble epoxide hydrolase in renal tubular epithelial cells regulates macrophage infiltration and polarization in IgA nephropathy

2018 ◽  
Vol 315 (4) ◽  
pp. F915-F926 ◽  
Author(s):  
Qian Wang ◽  
Yan Liang ◽  
Yingjin Qiao ◽  
Xiangya Zhao ◽  
Yi Yang ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Epoxide Hydrolase ◽  
Culture Media ◽  
Macrophage Polarization ◽  
Soluble Epoxide Hydrolase ◽  
Inflammatory Factor ◽  
M1 Polarization ◽  
Renal Tubulointerstitial Fibrosis ◽  
New Strategy ◽  
Renal Tubular

Tubulointerstitial inflammatory cell infiltration and activation contribute to kidney inflammation and fibrosis. Epoxyeicosatrienoic acids (EETs), which are rapidly metabolized to dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase (sEH), have multiple biological functions, including vasodilation, anti-inflammatory action, and others. Inhibition of sEH has been demonstrated to attenuate inflammation in many renal disease models. However, the relationship between sEH expression and macrophage polarization in the kidney remains unknown. In this study, we investigated the relationships between the level of sEH and clinical and pathological parameters in IgA nephropathy. The level of sEH expression positively correlated with proteinuria and infiltration of macrophages. sEH-positive tubules were found to be surrounded by macrophages. Furthermore, we found that incubation of immortalized human proximal tubular HK-2 cells with total urinary protein and overexpression of sEH promoted inflammatory factor production, which was associated with M1 polarization. We also exposed RAW264.7 mouse leukemic monocytes/macrophages to different HK-2 cell culture media conditioned by incubation with various substances affecting sEH amount or activity. We found that the upregulation of sEH promoted M1 polarization. However, pharmacological inhibition of sEH and supplementation with EETs reversed the conditioning effects of urinary proteins by inhibiting M1 polarization through the NF-κB pathway and stimulating M2 polarization through the phosphatidylinositol 3-kinase pathway. These data suggest that inhibition of sEH could be a new strategy to prevent the progression of inflammation and to attenuate renal tubulointerstitial fibrosis.

Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy

2015 ◽  
Vol 308 (8) ◽  
pp. C621-C630 ◽  
Author(s):  
Jun Liu ◽  
Ju-Rong Yang ◽  
Xiang-Mei Chen ◽  
Guang-Yan Cai ◽  
Li-Rong Lin ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial Cells ◽  
Gene Silencing ◽  
Er Stress ◽  
Premature Senescence ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Activation Of Transcription ◽  
Renal Tubular ◽  
Transcription Factor 4

Premature senescence is an important event during diabetic nephropathy (DN) progression. Here, we investigated the role of endoplasmic reticulum (ER) stress-regulated activation of transcription factor 4 (ATF4)/p16 signaling in the premature senescence of renal tubular epithelial cells (RTECs) during DN development. In the renal tissues of Type 2 DN patients, we detected an increased number of senescent cells; elevated deposition of advanced glycation end products (AGEs); upregulated expression of ER stress marker, glucose-regulated protein 78; as well as overexpression of ATF4 and p16. Similarly, these phenomena were also observed in cultured mouse RTECs following AGE treatment. Interestingly, AGE-induced p16 expression and premature senescence were successfully attenuated by ER stress inhibitor and ATF4 gene silencing. Moreover, AGE-induced premature senescence was mimicked by ER stress inducers and ATF4 overexpression, while suppressed by p16 gene silencing. In addition, ER stress inducers can augment ATF4 expression. Therefore, our results demonstrate that the ER stress-regulated ATF4/p16 pathway is involved in the premature senescence of RTECs during DN progression.

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