scholarly journals Connexin 43 prevents the progression of diabetic renal tubulointerstitial fibrosis by regulating the SIRT1-HIF-1α signaling pathway

2020 ◽  
Vol 134 (13) ◽  
pp. 1573-1592
Author(s):  
Xiaohong Sun ◽  
Kaipeng Huang ◽  
Xiao Haiming ◽  
Zeyuan Lin ◽  
Yan Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Pathological Process ◽  
Tubulointerstitial Fibrosis ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular

Abstract Hyperglycemia-induced renal epithelial-to-mesenchymal transition (EMT) is a key pathological factor in diabetic renal tubulointerstitial fibrosis (RIF). Our previous studies have shown that connexin 43 (Cx43) activation attenuated the development of diabetic renal fibrosis. However, whether Cx43 regulates the EMT of renal tubular epithelial cells (TECs) and the pathological process of RIF under the diabetic conditions remains to be elucidated. In the present study, we identified that Cx43 protein expression was down-regulated in the kidney tissues of db/db mice as well as in high glucose (HG)-induced NRK-52E cells. Overexpression of Cx43 improved renal function in db/db spontaneous diabetic model mice, increased SIRT1 levels, decreased hypoxia-inducible factor (HIF)-1α expression, and reduced production of EMT markers and extracellular matrix (ECM) components. Additionally, Cx43 overexpression inhibited the EMT process and reduced the expression of ECM components such as fibronectin (FN), Collagen I, and Collagen IV in HG-induced NRK-52E cells, whereas Cx43 deficiency had the opposite effects. Mechanistically, Cx43 in a carboxyl-terminal signal transduction-dependent manner could up-regulate SIRT1 expression and enhance SIRT1-dependent deacetylation of HIF-1α to reduce HIF-1α activity, which eventually ameliorated renal EMT and diabetic RIF. Our study indicates the essential role of Cx43 in regulating renal EMT and diabetic RIF via regulating the SIRT1-HIF-1α signaling pathway and provides an experimental basis for Cx43 as a potential target for diabetic nephropathy (DN).

scholarly journals Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

2021 ◽  
Vol 38 (2) ◽  
Author(s):  
Wenqian Zheng ◽  
Jinhui Hu ◽  
Yiming Lv ◽  
Bingjun Bai ◽  
Lina Shan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Dependent Signaling Pathway ◽  
Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

2021 ◽  
Vol 19 (4) ◽  
pp. 508-513
Author(s):  
Jinhao Wu ◽  
Chao Huang ◽  
Gang Kan ◽  
Hanyu Xiao ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Therapeutic Drugs ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Renal Tubular ◽  
Antioxidant Effects ◽  
Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

Abstract 132: Hypoxia-inducible Factor Prolyl-hydroxylase-2 Mediates Transforming Growth Factor Beta 1-induced Epithelial-mesenchymal Transition In Renal Tubular Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Weiqing Han ◽  
Jun-Pin Hu ◽  
Pin-Lan Li ◽  
Ningjun Li
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Hypoxia Inducible Factor ◽  
Mesenchymal Transition ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Transforming growth factor beta 1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) in kidney epithelial cells plays a key role in renal tubulointerstitial fibrosis in chronic kidney diseases. As hypoxia-inducible factor (HIF)-1α is found to mediate TGFβ1 signaling pathway, we tested the hypothesis that HIF-1α and its upstream regulator prolyl hydroxylase domain-containing proteins (PHDs) are involved in TGFβ1-induced EMT in renal tubular cells. Our results showed that TGFβ1 treatment for 48 h stimulated EMT in cultured renal tubular cells as indicated by the decrease in epithelial marker P-cadherin from 1.0 ± 0.02 to 0.40 ± 0.05 ( P < 0.05), and the increase in mesenchymal markers α-smooth muscle actin (2.14 ± 0.32 fold, P < 0.05) and fibroblast-specific protein (2.0 ± 0.17 fold, P < 0.05) as shown in Western blot assay. Meanwhile, TGFβ1 time-dependently increased HIF-1α, which reached its maximum value (2.36 ± 0.2 fold, P < 0.05) at 24 h, and that HIF-1α siRNA significantly inhibited TGFβ1-induced EMT, suggesting that HIF-1α mediated TGFβ1 induced-EMT. Real-time PCR showed that PHD1 and PHD2, rather than PHD3, could be detected, with PHD2 as the predominant form of PHDs (PHD1 : PHD2 = 0.21:1.0). Importantly, TGFβ1 time-dependently decreased PHD2 mRNA and protein level, which reached their maximum value from 1.0 ± 0.15 to 0.45 ± 0.08 ( P < 0.05) for mRNA at 16 h and from 1.0 ± 0.08 to 0.26 ± 0.08 ( P < 0.05) for protein at 24 h, respectively. In contrast, TGFβ1 had no effect on PHD1 mRNA and protein levels. Furthermore, over-expression of PHD2 transgene almost fully prevented TGFβ1-induced HIF-1α accumulation and EMT marker changes, indicating that PHD2 is involved in TGFβ1-induced EMT. Finally, Smad2 inhibitor SB431542 prevented TGFβ1-induced PHD2 decrease, suggesting that Smad2 may mediate TGFβ1-induced EMT through PHD2/HIF-1α. It is concluded that TGFβ1 decreased PHD2 expression via a Smad2-dependent signaling pathway, thereby leading to HIF-1α accumulation and EMT in renal tubular cells. The present study suggests that PHD2/HIF-1α is a novel signaling pathway mediating the fibrogenic effect of TGFβ1 and that manipulating PHD2/HIF-1α pathway may be used as a therapeutic strategy in chronic kidney diseases. (support: NIH grant HL89563 and HL106042)

Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition

2015 ◽  
Vol 93 (7) ◽  
pp. 759-772 ◽  
Author(s):  
Min-Kyung Kang ◽  
Sin-Hye Park ◽  
Yean-Jung Choi ◽  
Daekeun Shin ◽  
Young-Hee Kang
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Tubulointerstitial Fibrosis ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis

The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression

2012 ◽  
Vol 302 (3) ◽  
pp. F369-F379 ◽  
Author(s):  
Mingxia Xiong ◽  
Lei Jiang ◽  
Yang Zhou ◽  
Wenjing Qiu ◽  
Li Fang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Renal Tubular ◽  
Novel Therapeutic Strategies ◽  
Tgf Β1

Most chronic kidney injuries inevitably progress to irreversible renal fibrosis. Tubular epithelial-to-mesenchymal transition (EMT) is recognized to play pivotal roles in the process of renal fibrosis. However, a comprehensive understanding of the pathogenesis of renal scar formation and progression remains an urgent task for renal researchers. The endogenously produced microRNAs (miRNAs), proved to play important roles in gene regulation, probably regulate most genes involved in EMT. In this study, we applied microarray analysis to investigate the expression profiles of miRNA in murine interstitial fibrotic kidneys induced by unilateral ureteral obstruction (UUO). It was found that miR-200a and miR-141, two members of the miR-200 family, were downregulated at the early phase of UUO. In TGF-β1-induced tubular EMT in vitro, it was also found that the members of the miR-200 family were downregulated in a Smad signaling-dependent manner. It was demonstrated that the miR-200 family was responsible for protecting tubular epithelial cells from mesenchymal transition by target suppression of zinc finger E-box-binding homeobox (ZEB) 1 and ZEB2, which are E-cadherin transcriptional repressors. The results suggest that downregulation of the miR-200 family initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which might provide important targets for novel therapeutic strategies.

scholarly journals Metformin attenuates renal tubulointerstitial fibrosis via upgrading autophagy in the early stage of diabetic nephropathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fengzhen Wang ◽  
Haihan Sun ◽  
Bangjie Zuo ◽  
Kun Shi ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial Cells ◽  
Early Stage ◽  
Tubulointerstitial Fibrosis ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular

AbstractThis study aimed at comparing the effects of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluating the mechanism in high glucose (HG)-treated renal tubular epithelial cells (RTECs) in vitro. Sprague–Dawley (SD) rats were used to establish a model of DN, and the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified using histological analysis, immunohistochemistry, and immunoblot. The underlying relationship between autophagy and DN, and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) were investigated. Metformin markedly improved renal function and histological restoration of renal tissues, especially in the early stages of DN, with a significant increase in autophagy and a decrease in the expression of fibrotic biomarkers (fibronectin and collagen I) in renal tissue. Under hyperglycemic conditions, renal tubular epithelial cells inactivated p-AMPK and activated partial EMT. Metformin-induced AMPK significantly ameliorated renal autophagic function, inhibited the partial EMT of RTECs, and attenuated TIF, all of which effectively prevented or delayed the onset of DN. This evidence provides theoretical and experimental basis for the following research on the potential clinical application of metformin in the treatment of diabetic TIF.

scholarly journals Metformin Attenuates Renal Tubulointerstitial Fibrosis via Upgrading Autophagy in the Early Stage of Diabetic Nephropathy

2021 ◽  
Author(s):  
Fengzhen Wang ◽  
Dong Sun ◽  
Haihan Sun ◽  
Bangjie Zuo ◽  
Kun Shi ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Early Stage ◽  
Renal Tissue ◽  
Tubulointerstitial Fibrosis ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis

Abstract The aim of the study was to compare the role of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluate its mechanism in high-glucose-treated Renal tubular epithelial cells (RTECs) in vitro. Sprague-Dawley (SD) rats were used to establish model of DN, then the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified via histological analysis, immunohistochemistry, and immunoblot. The underlying relationship between autophagy and DN was analyzed and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) was detected. Metformin markedly improved renal function and showed histological restoration of renal tissues especially in the early stage of DN, with a significant improvement of autophagy and a low expression of fibrotic biomarkers (Fibronectin and Collagen I) in renal tissue. RTECs under hyperglycemic conditions exhibited inactivation of p-AMPK and activation of EMT. But the promotion of AMPK activated by metformin significantly improved renal autophagic function, inhibited the EMT of RTECs, attenuated TIF, so as to effectively prevent or delay the course of DN. This evidence provided theoretical and experimental basis for the following research on the potential clinical usefulness of metformin for the treatment of diabetic TIF.

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.

Sign in / Sign up

Export Citation Format

Share Document