scholarly journals Erythropoietin Inhibits Hypoxia–Induced Epithelial-To-Mesenchymal Transition via Upregulation of miR-200b in HK-2 Cells

2017 ◽  
Vol 42 (1) ◽  
pp. 269-280 ◽  
Author(s):  
Jiuxu Bai ◽  
Xiao Xiao ◽  
Xiaoling Zhang ◽  
Hanmin Cui ◽  
Junfeng Hao ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Tubular Epithelial Cell ◽  
Epithelial Cell Line ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Proximal Tubular ◽  
Renal Tubular

Background/Aims: Renal tubular epithelial-mesenchymal transition (EMT) is regarded as an important factor leading to renal interstitial fibrosis. Erythropoietin (EPO) has been reported to attenuate renal fibrosis. The mechanism underlying this protective effect of EPO remains unclear. In this study, we aim to identify possible mechanisms of the EPO renoprotective effect. Methods: Hypoxia was induced in vitro by incubating human proximal tubular epithelial cell line HK-2 cells in 1% O2 and 5% CO2. Western blotting and reverse transcription polymerase chain reaction analyses were used to evaluate the expression of epithelial and mesenchymal markers in the cell samples. The expression of miR-200b in the HK-2 cells under hypoxia or treatment with EPO was examined. Results: EPO represses hypoxia-induced EMT by upregulating miR-200b in HK-2 cells. Overexpression of miR-200b represses the effect of ETS proto-oncogene 1 (Ets-1)-induced EMT in HK-2 cells. Conclusion: miR-200 mediates the protective effects of EPO on EMT in hypoxic HK-2 cells. EPO attenuated hypoxia-induced EMT by increasing miR-200 expression via the repression of Ets-1.

scholarly journals Emodin Ameliorates High Glucose Induced-Podocyte Epithelial-Mesenchymal Transition In-Vitro and In-Vivo

2015 ◽  
Vol 35 (4) ◽  
pp. 1425-1436 ◽  
Author(s):  
Tingfang Chen ◽  
Li Yang Zheng ◽  
Wenzhen Xiao ◽  
Dingkun Gui ◽  
Xiaoxia Wang ◽  
...  
Keyword(s):  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Option ◽  
Diabetic Rats ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Epithelial Marker

Background: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Methods: Conditionally immortalized mouse podocytes were exposed to HG with 30μg /ml of EMO and 1μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg-1· d-1 and QLT0267 at 10 mg· kg-1· w-1 p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. Results: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. Conclusion: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD.

scholarly journals Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype

2018 ◽  
Author(s):  
Eduard Sarró ◽  
Mónica Durán ◽  
Ana Rico ◽  
Anthony J. Croatt ◽  
Karl A. Nath ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Cell Plasticity ◽  
Ppiase Activity ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Epithelial Phenotype ◽  
Proximal Tubular ◽  
Renal Tubular

AbstractCyclophilins (Cyp) are peptidil-prolyl-isomerases and the intracellular receptors for the immunosuppressant Cyclosporine-A (CsA), which produces epithelial-mesenchymal-transition (EMT) and renal tubule-interstitial fibrosis. Since CsA inhibits Cyp enzymatic activity, we hypothesized that Cyp could be involved in EMT and fibrosis. Here, we demonstrate that CypB is a critical regulator of tubule epithelial cell plasticity on the basis that: i) CypB silencing caused epithelial differentiation in proximal tubule-derived HK-2 cells, ii) CypB silencing prevented TGFβ-induced EMT in HK-2, and iii) CypB knockdown mice exhibited reduced UUO-induced inflammation and kidney fibrosis. By contrast, silencing of CypA induces a more undifferentiated phenotype and favors TGFβ effects. EMT mediators Slug and Snail were up-regulated in CypA-silenced cells, while in CypB silencing, Slug, but not Snail, was down-regulated; thus, reinforcing the role of Slug in kidney fibrosis. CypA regulates Slug through its PPIase activity whereas CypB depends on its ER location, where interacts with calreticulin, a calcium modulator which is involved in TGFβ signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating proximal tubular cell plasticity.

scholarly journals USP36-Mediated Deubiquitination of DOCK4 Contributes to the Diabetic Renal Tubular Epithelial Cell Injury via Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Suwei Zhu ◽  
Shaoshuai Hou ◽  
Yao Lu ◽  
Wei Sheng ◽  
Zhengguo Cui ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Injury ◽  
Tubular Epithelial Cell ◽  
Current Treatment ◽  
Nucleotide Exchange ◽  
Mesenchymal Transition ◽  
Renal Tubular

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease but the efficacy of current treatment remains unsatisfactory. The pathogenesis of DKD needs a more in-depth research. Ubiquitin specific proteases 36 (USP36), a member of deubiquitinating enzymes family, has aroused wide concerns for its role in deubiquitinating and stabilizing target proteins. Nevertheless, the role of USP36 in diabetes has never been reported yet. Herein, we identified an increased expression of USP36 both in vitro and in vivo in diabetic renal tubular epithelial cells (TECs), and its overexpression is related to the enhanced epithelial-to-mesenchymal transition (EMT). Further investigation into the mechanisms proved that USP36 could directly bind to and mediate the deubiquitination of dedicator of cytokinesis 4 (DOCK4), a guanine nucleotide exchange factor (GEF) that could activate Wnt/β-catenin signaling pathway and induce EMT. Our study revealed a new mechanism that USP36 participates in the pathogenesis of DKD, and provided potential intervening targets accordingly.

scholarly journals Knockdown of ANGPTL2 Protects Renal Tubular Epithelial Cells Against Hypoxia/Reoxygenation-Induced Injury via Suppressing TLR4/NF-κB Signaling Pathway and Activating Nrf2/HO-1 Signaling Pathway

2020 ◽  
Vol 29 ◽  
pp. 096368972094666
Author(s):  
Heli Xiang ◽  
Wujun Xue ◽  
Yang Li ◽  
Jin Zheng ◽  
Chenguang Ding ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion ◽  
Tubular Epithelial Cell ◽  
Epithelial Cell Line ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
Treatment And Prevention ◽  
Renal Tubular ◽  
Hypoxia Reoxygenation

Renal ischemia/reperfusion (I/R) injury is a particular threat faced by clinicians in kidney transplantation. Previous studies have confirmed the importance of oxidative stress and inflammation in the pathogenesis of I/R injury. Angiopoietin-like protein 2 (ANGPTL2) belongs to the angiopoietin-like family and has been found to be involved in the regulation of kidney function as well as oxidative and inflammatory response. In the present study, we aimed to evaluate the role of ANGPTL2 in renal I/R injury in vitro. The human proximal tubular epithelial cell line (HK-2 cells) was subjected to hypoxia/ reoxygenation (H/R) to mimic I/R injury in vitro. We found that the expression level of ANGPTL2 was markedly increased in H/R-induced HK-2 cells. Knockdown of ANGPTL2 improved the decreased cell viability of HK-2 cells in response to H/R stimulation. Knockdown of ANGPTL2 significantly inhibited the H/R-caused increase in levels of reactive oxygen species, malondialdehyde, and proinflammatory cytokines, including interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha, as well as a decrease in superoxide dismutase activity in the HK-2 cells. Besides, the increased bax expression and caspase-3 activity and decreased bcl-2 expression in H/R-induced HK-2 cells were also attenuated by knockdown of ANGPTL2. Moreover, ANGPTL2 overexpression showed the opposite effects. Further mechanism investigations proved that the activation of Nrf2/HO-1 signaling pathway and the inhibition of toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway were both implicated in the renal-protective effects of ANGPTL2 knockdown on H/R-induced HK-2 cells. Collectively, these findings suggested that ANGPTL2 might be a new possible target for the treatment and prevention of renal I/R injury.

Blocking core fucosylation of TGF-β1 receptors downregulates their functions and attenuates the epithelial-mesenchymal transition of renal tubular cells

2011 ◽  
Vol 300 (4) ◽  
pp. F1017-F1025 ◽  
Author(s):  
Hongli Lin ◽  
Dapeng Wang ◽  
Taihua Wu ◽  
Cui Dong ◽  
Nan Shen ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Cell Model ◽  
Mesenchymal Transition ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Core Fucosylation ◽  
Tgf Β1

Posttranslational modification of proteins could regulate their multiple biological functions. Transforming growth factor-β receptor I and II (ALK5 and TGF-βRII), which are glycoproteins, play important roles in the renal tubular epithelial-mesenchymal transition (EMT). In the present study, we examined the role of core fucosylation of TGF-βRII and ALK5, which is regulated by α-1,6 fucosyltransferase (Fut8), in the process of EMT of cultured human renal proximal tubular epithelial (HK-2) cells. The typical cell model of EMT induced by TGF-β1 was constructed to address the role of core fucosylation in EMT. Core fucosylation was found to be essential for both TGF-βRII and ALK5 to fulfill their functions, and blocking it with Fut8 small interfering RNA greatly reduced the phosphorylation of Smad2/3 protein, caused the inactivation of TGF-β/Smad2/3 signaling, and resulted in remission of EMT. More importantly, even with high levels of expressions of TGF-β1, TGF-βRII, and ALK5, blocking core fucosylation also could attenuate the EMT of HK-2 cells. Thus blocking core fucosylation of TGF-βRII and ALK5 may attenuate EMT independently of the expression of these proteins. This study may provide new insight into the role of glycosylation in renal interstitial fibrosis. Furthermore, core fucosylation may be a novel potential therapeutic target for treatment of renal tubular EMT.

scholarly journals Effect of Huai Qi Huang on Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells through miR-200a

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jinyun Pu ◽  
Yu Zhang ◽  
Jianhua Zhou
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanism ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Renal Tubular

Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is a vital mechanism of renal fibrosis. Mounting evidence suggests that miR-200a expression decreases in tubular epithelial cells in unilateral ureteral obstruction (UUO) rats. Moreover, it has been demonstrated that Huai Qi Huang (HQH) can ameliorate tubulointerstitial damage in adriamycin nephrosis and delay kidney dysfunction in primary glomerular disease. However, the effect of HQH on EMT of tubular epithelial cells in UUO rats and its molecular mechanism is unclear. In order to explore the effect of HQH on EMT and its molecular mechanism in renal fibrosis,in vitroandin vivoexperiments were performed in our study. Our results showed that HQH increased miR-200a expression in UUO rats and in TGF-β1 stimulated NRK-52E cells. Meanwhile, HQH decreased ZEB1 and ZEB2 (the transcriptional repressors of E-cadherin),α-SMA expression in renal tubular epithelial cellsin vitroandin vivo. Furthermore, we found that HQH protected kidney from fibrosis in UUO rats. The results demonstrated that HQH regulated miR-200a/ZEBs pathway and inhibited EMT process, which may be a mechanism of protecting effect on tubular cells in renal fibrosis.

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