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 Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells.

1998 ◽  
Vol 9 (12) ◽  
pp. 2283-2290
Author(s):  
B Beck-Schimmer ◽  
B Oertli ◽  
T Pasch ◽  
R P Wüthrich
Keyword(s):  
Protein Expression ◽  
Renal Injury ◽  
De Novo ◽  
Kidney Diseases ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Mrna And Protein Expression ◽  
Renal Tubular

Hyaluronan (HA) is a nonsulfated glycosaminoglycan that accumulates in the renal interstitium in immune-mediated kidney diseases. The functional significance of such HA deposition in the kidney has not been elucidated. Several studies have suggested that HA may exhibit proinflammatory effects. Since chemokines such as monocyte chemoattractant protein-1 (MCP-1) play an important role in the recruitment of leukocytes in renal injury, this study tested whether HA and its fragments could promote MCP-1 production by renal parenchymal cells. Mouse cortical tubular cells were stimulated with fragmented HA or with high molecular weight HA (Healon) in vitro and were examined for MCP-1 expression. Fragmented HA, but not Healon, increased MCP-1 mRNA within 30 min with a peak after 2 h. In addition, a 10-fold increase of MCP-1 protein in the supernatant was found after a 6-h stimulation with fragmented HA. The enhanced MCP-1 mRNA and protein expression in response to HA was dose-dependent between 1 and 100 microg/ml. Upregulation of MCP-1 protein production could be blocked by preincubation with actinomycin D or cycloheximide, suggesting that MCP-1 mRNA and protein expression in response to HA are based on de novo synthesis. The HA-stimulated MCP-1 production was also inhibited with anti-CD44 antibodies, suggesting that MCP-1 is upregulated at least in part by signaling through CD44. In summary, fragmented HA markedly stimulates renal tubular MCP-1 production by mechanisms that involve binding to the HA receptor CD44. It is hypothesized that the accumulation of HA in immune renal injury could participate in the recruitment and activation of inflammatory cells in vivo through production of MCP-1.

scholarly journals Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto–Kakizaki rats

2008 ◽  
Vol 116 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Jeffrey J. Olearczyk ◽  
Jeffrey E. Quigley ◽  
Bradford C. Mitchell ◽  
Tatsuo Yamamoto ◽  
In-Hae Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Histological Evaluation ◽  
Kidney Cortex ◽  
Tubular Damage ◽  
Dodecanoic Acid ◽  
Monocyte Chemoattractant Protein 1 ◽  
Gk Rats

Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto–Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118±2 mmHg to 182±20 and 187±6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.

scholarly journals Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

2009 ◽  
Vol 297 (4) ◽  
pp. F996-F1005 ◽  
Author(s):  
Maoyin Pang ◽  
Jagan Kothapally ◽  
Haiping Mao ◽  
Evelyn Tolbert ◽  
Murugavel Ponnusamy ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Trichostatin A ◽  
Smooth Muscle Actin ◽  
Tubular Cell ◽  
Obstructive Nephropathy ◽  
Renal Tubular Cell ◽  
Fibroblast Activation ◽  
Renal Tubular

Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) . α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.

scholarly journals Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

2020 ◽  
Author(s):  
Wei Chen ◽  
Yilan Shen ◽  
Jiajun Fan ◽  
Xian Zeng ◽  
Xuyao Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Metabolic Reprogramming ◽  
Protective Effects ◽  
Interleukin 22 ◽  
Renal Tubular ◽  
Stage Renal Disease ◽  
End Stage

AbstractKidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

Effect of Forkhead Box O1 in Renal Tubular Epithelial Cells on Endotoxin-Induced Acute Kidney Injury

2020 ◽  
Author(s):  
Mengxi Zhang ◽  
Wei Dong ◽  
Zhilian Li ◽  
Zhenmeng Xiao ◽  
Zhiyong Xie ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Mitochondrial Damage ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Forkhead Box ◽  
Renal Tubular

Mitochondrial damage in renal tubular epithelial cells (RTECs) is a hallmark of endotoxin-induced acute kidney injury (AKI). Forkhead box O1 (FOXO1) is responsible for regulating mitochondrial function and is involved in several kidney diseases. Herein, we investigated the effect of FOXO1 on endotoxin-induced AKI and the related mechanism. In vivo, FOXO1 downregulation in mouse RTECs and mitochondrial damage were found in endotoxin-induced AKI. Overexpression of FOXO1 by kidney focal adeno-associated virus (AAV) delivery improved renal function and reduced mitochondrial damage. PGC1-α, a master regulator of mitochondrial biogenesis and function, was reduced in endotoxin-induced AKI, but the reduction was reversed by FOXO1 overexpression. In vitro, exposure to LPS led to a decline in HK-2 cell viability, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of FOXO1, PGC1-α and mitochondrial complex I/V. Moreover, overexpression of FOXO1 in HK-2 cells increased HK-2 cell viability and PGC1-α expression, and it alleviated the mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA treatment decreased PGC1-α expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed that FOXO1 bound to the PGC1-α promoter in HK-2 cells. In conclusion, downregulation of FOXO1 in RTECs mediated endotoxin-induced AKI and mitochondrial damage. Overexpression of FOXO1 could improve renal injury and mitochondrial dysfunction, and this effect occurred at least in part as a result of PGC1-α signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.

scholarly journals Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury

FEBS Journal ◽  
2017 ◽  
Vol 284 (13) ◽  
pp. 1970-1986 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Shinichiro Koike ◽  
Samah Chahed ◽  
Yi Zhao ◽  
Santana Bachaalany ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epoxide Hydrolase ◽  
Kidney Injury ◽  
Soluble Epoxide Hydrolase

scholarly journals Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Akito Maeshima ◽  
Shunsuke Takahashi ◽  
Masao Nakasatomi ◽  
Yoshihisa Nojima
Keyword(s):  
Stem Cell ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Cell Populations ◽  
Renal Tubules ◽  
Stem Cell Markers ◽  
Tubular Epithelium ◽  
Tubular Cells ◽  
Renal Tubular Epithelium ◽  
Renal Tubular

Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans.

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.

scholarly journals Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes

2011 ◽  
Vol 301 (5) ◽  
pp. R1307-R1317 ◽  
Author(s):  
Ahmed A. Elmarakby ◽  
Jessica Faulkner ◽  
Mohammed Al-Shabrawey ◽  
Mong-Heng Wang ◽  
Krishna Rao Maddipati ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Renal Injury ◽  
Epoxide Hydrolase ◽  
Thiobarbituric Acid ◽  
Soluble Epoxide Hydrolase ◽  
Nuclear Factor Κb ◽  
Organ Damage ◽  
Protective Effects ◽  
Renal Inflammation ◽  
Monocyte Chemoattractant Protein 1

Studies suggest that soluble epoxide hydrolase (sEH) inhibition reduces end-organ damage in cardiovascular diseases. We hypothesize that sEH gene ( Ephx2) knockout (KO) improves endothelial function and reduces renal injury in streptozotocin-induced diabetes. After 6 wk of diabetes, afferent arteriolar relaxation to acetylcholine was impaired in diabetic wild-type (WT) mice, as the maximum relaxation was 72% of baseline diameter in the WT but only 31% in the diabetic mice. Ephx2 KO improved afferent arteriolar relaxation to acetylcholine in diabetes as maximum relaxation was 58%. Urinary monocyte chemoattractant protein-1 (MCP-1) excretion significantly increased in diabetic WT mice compared with control (868 ± 195 vs. 31.5 ± 7 pg/day), and this increase was attenuated in diabetic Ephx2 KO mice (420 ± 98 pg/day). The renal phospho-IKK-to-IKK ratio and nuclear factor-κB were significantly decreased, and hemeoxygenase-1 (HO-1) expression increased in diabetic Ephx2 KO compared with diabetic WT mice. Renal NADPH oxidase and urinary thiobarbituric acid reactive substances excretion were reduced in diabetic Ephx2 KO compared with diabetic WT mice. Albuminuria was also elevated in diabetic WT mice compared with control (170 ± 43 vs. 37 ± 13 μg/day), and Ephx2 KO reduced this elevation (50 ± 15 μg/day). Inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) also reduced renal inflammation and injury in diabetic WT mice. Furthermore, inhibition of HO with stannous mesoporphyrin negated the reno-protective effects of tAUCB or Ephx2 KO during diabetes. These data demonstrate that Ephx2 KO improves endothelial function and reduces renal injury during diabetes. Additionally, our data also suggest that activation of HO-1 contributes to improved renal injury in diabetic Ephx2 KO mice.

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