Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy

2014 ◽  
Vol 306 (5) ◽  
pp. F486-F495 ◽  
Author(s):  
Jin-yang Wang ◽  
Yan-bin Gao ◽  
Na Zhang ◽  
Da-wei Zou ◽  
Li-ping Xu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Physiological Role ◽  
Structure And Function ◽  
Clearance Ratio ◽  
Mesenchymal Transition ◽  
Renal Structure ◽  
And Function ◽  
E Cadherin

Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-β1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.

scholarly journals Radix Rehmanniae and Corni Fructus against Diabetic Nephropathy via AGE-RAGE Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Jing Chen ◽  
Yuping Chen ◽  
Anmei Shu ◽  
Jinfu Lu ◽  
Qiu Du ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Animal Experiments ◽  
Structure And Function ◽  
Metabolic Parameters ◽  
Network Pharmacology ◽  
Active Compounds ◽  
Renal Structure ◽  
Corni Fructus ◽  
And Function

Background and Aims. Radix Rehmanniae and Corni Fructus (RC) have been widely applied to treat diabetic nephropathy (DN) for centuries. But the mechanism of how RC plays the therapeutic role against DN is unclear as yet. Methods. The information about RC was obtained from a public database. The active compounds of RC were screened by oral bioavailability (OB) and drug-likeness (DL). Gene ontology (GO) analysis was performed to realize the key targets of RC, and an active compound-potential target network was created. The therapeutic effects of RC active compounds and their key signal pathways were preliminarily probed via network pharmacology analysis and animal experiments. Results. In this study, 29 active compounds from RC and 64 key targets related to DN were collected using the network pharmacology method. The pathway enrichment analysis showed that RC regulated advanced glycosylation end product (AGE-) RAGE and IL-17 signaling pathways to treat DN. The animal experiments revealed that RC significantly improved metabolic parameters, inflammation renal structure, and function to protect the kidney against DN. Conclusions. The results revealed the relationship between multicomponents and multitargets of RC. The administratiom of RC might remit the DM-induced renal damage through the AGE-RAGE signaling pathway to improve metabolic parameters and protect renal structure and function.

scholarly journals Nrf2-Heme Oxygenase-1 Attenuates High-Glucose-Induced Epithelial-to-Mesenchymal Transition of Renal Tubule Cells by Inhibiting ROS-Mediated PI3K/Akt/GSK-3β Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jong Ho Shin ◽  
Kyeong Min Kim ◽  
Jin Uk Jeong ◽  
Jae Min Shin ◽  
Ju Hyung Kang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Glycogen Synthase ◽  
Heme Oxygenase 1 ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Nrf2 Activator ◽  
Hk2 Cells ◽  
E Cadherin

Background. Epithelial-to-mesenchymal transition (EMT) is thought to play a significant role in the advancement to chronic kidney disease and contributes to the deposition of extracellular matrix proteins and renal fibrosis relating to diabetic nephropathy. Method. We studied the effect of Nrf2-HO-1 signaling on high-glucose- (HG-) induced EMT in normal human tubular epithelial cells, that is, HK2 cells. In short, we treated HK2 cells with HG and sulforaphane (SFN) as an Nrf2 activator. EMT was evaluated by the expression activity of the epithelial marker E-cadherin and mesenchymal markers such as vimentin and fibronectin. Results. Exposure of HK2 cells to HG (60 mM) activated the expression of vimentin and fibronectin but decreased E-cadherin. Treatment of HK2 cells with SFN caused HG-induced attenuation in EMT markers with activated Nrf2-HO-1. We found that SFN decreased HG-induced production of reactive oxygen species (ROS), phosphorylation of PI3K/Akt at serine 473, and inhibitory phosphorylation of serine/threonine kinase glycogen synthase kinase-3β (GSK-3β) at serine 9. Subsequently, these signaling led to the downregulation of the Snail-1 transcriptional factor and the recovery of E-cadherin. Conclusion. The present study suggests that Nrf2-HO-1 signaling has an inhibitory role in the regulation of EMT through the modulation of ROS-mediated PI3K/Akt/GSK-3β activity, highlighting Nrf2-HO-1 and GSK-3β as potential therapeutic targets in diabetic nephropathy.

Prostaglandin D2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in MDCK cells

2006 ◽  
Vol 291 (6) ◽  
pp. F1332-F1342 ◽  
Author(s):  
Aihua Zhang ◽  
Zheng Dong ◽  
Tianxin Yang
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mdck Cells ◽  
Smooth Muscle Actin ◽  
Antioxidant Property ◽  
Prostaglandin D2 ◽  
Mesenchymal Transition ◽  
Species Production ◽  
Tgf Β1 ◽  
E Cadherin

In a separate study, we identified PGE2 as a potent inhibitor of TGF-β1-induced epithelial-mesenchymal transition (EMT) in cultured Madin-Darby canine kidney (MDCK) cells (Zhang A, Wang M-H, Dong Z, and Yang T. Am J Physiol Renal Physiol 291: F1323–F1331, 2006). This finding prompted us to examine the roles of other prostanoids: PGD2, PGF2α, PGI2, and thromboxane A2 (TXA2). Treatment with 10 ng/ml TGF-β1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and activation of α-smooth muscle actin (α-SMA). Treatment with PGD2 remarkably preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of α-SMA. In contrast, PGF2α, carbocyclic thromboxane A2, PGI2 and its stable analog beraprost were without an effect. MDCK cells expressed DP1 and DP2 receptors; however, the effect of PGD2 was neither prevented by DP1 antagonist BW-A868C or DP2 antagonist BAY-u3405 nor was mimicked by DP1 agonist BW-245C. cAMP-elevating agents forskolin and 8-Br-cAMP blocked EMT. However, cAMP blockers H89 and Rp-cAMP failed to block the effect of PGD2. PGD2 did not seem to act via its metabolites as 15-deoxy-Delta( 12 , 14 )-prostaglandin J2 (15d-PGJ2) levels in the medium following incubation with 3 μM PGD2 were well below the values predicted from the cross activity of the assay. Exposure to TGF-β1 induced a threefold increase in reactive oxygen species production that was completely abolished by PGD2. We conclude that 1) PGD2, but not PGI2, PGF2α, and TXA2 inhibit EMT, 2) PGD2 inhibits EMT independently of DP1 and DP2 receptors, and 3) PGD2 exhibits antioxidant property which may, in part, account for the antifibrotic action of this PG.

scholarly journals Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells

2012 ◽  
Vol 20 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Patsy S H Soon ◽  
Edward Kim ◽  
Cindy K Pon ◽  
Anthony J Gill ◽  
Katrina Moore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Flow Cytometric Analysis ◽  
Cancer Associated Fibroblasts ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Functional Changes ◽  
E Cadherin

Cancer-associated fibroblasts (CAFs) play a role in tumour initiation and progression, possibly by inducing epithelial-to-mesenchymal transition (EMT), a series of cellular changes that is known to underlie the process of metastasis. The aim of this study was to determine whether CAFs and surrounding normal breast fibroblasts (NBFs) are able to induce EMT markers and functional changes in breast epithelial cancer cells. Matched pairs of CAFs and NBFs were established from fresh human breast cancer specimens and characterised by assessment of CXCL12 levels, α-smooth muscle actin (α-SMA) levels and response to doxorubicin. The fibroblasts were then co-cultured with MCF7 cells. Vimentin and E-cadherin expressions were determined in co-cultured MCF7 cells by immunofluorescence and confocal microscopy as well as by western blotting and quantitative PCR. Co-cultured MCF7 cells were also assessed functionally by invasion assay. CAFs secreted higher levels of CXCL12 and expressed higher levels of α-SMA compared with NBFs. CAFs were also less sensitive to doxorubicin as evidenced by less H2AX phosphorylation and reduced apoptosis on flow cytometric analysis of Annexin V compared with NBFs. When co-cultured with MCF7 cells, there was greater vimentin and less E-cadherin expression as well as greater invasiveness in MCF7 cells co-cultured with CAFs compared with those co-cultured with NBFs. CAFs have the ability to induce a greater degree of EMT in MCF7 cell lines, indicating that CAFs contribute to a more malignant breast cancer phenotype and their role in influencing therapy resistance should therefore be considered when treating breast cancer.

scholarly journals Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF-β1-Induced Epithelial-to-Mesenchymal Transition

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Na Zhang ◽  
Yanbin Gao ◽  
Dawei Zou ◽  
Jinyang Wang ◽  
Jiaoyang Li ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Efficacy ◽  
Epithelial To Mesenchymal Transition ◽  
Chronic Kidney Failure ◽  
Clearance Ratio ◽  
Mesenchymal Transition ◽  
Urine Albumin ◽  
Chinese Herbal Compound

Diabetic nephropathy (DN) is a major cause of chronic kidney failure and characterized by interstitial and glomeruli fibrosis. Epithelial-to-mesenchymal transition (EMT) plays an important role in the pathogenesis of DN. Tong xinluo (TXL), a Chinese herbal compound, has been used in China with established therapeutic efficacy in patients with DN. To investigate the molecular mechanism of TXL improving DN, KK-Ay mice were selected as models for the evaluation of pathogenesis and treatment in DN. In vitro, TGF-β1 was used to induce EMT. Western blot (WB), immunofluorescence staining, and real-time polymerase chain reaction (RT-PCR) were applied to detect the changes of EMT markers in vivo and in vitro, respectively. Results showed the expressions of TGF-β1 and its downstream proteins smad3/p-smad3 were greatly reduced in TXL group; meantime, TXL restored the expression of smad7. As a result, the expressions of collagen IV (Col IV) and fibronectin (FN) were significantly decreased in TXL group. In vivo, 24 h-UAER (24-hour urine albumin excretion ratio) and BUN (blood urea nitrogen) were decreased and Ccr (creatinine clearance ratio) was increased in TXL group compared with DN group. In summary, the present study demonstrates that TXL successfully inhibits TGF-β1-induced epithelial-to-mesenchymal transition in DN, which may account for the therapeutic efficacy in TXL-mediated renoprotection.

Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 982-993 ◽  
Author(s):  
Jun-Sang Bae ◽  
Gwanghui Ryu ◽  
Ji Hye Kim ◽  
Eun Hee Kim ◽  
Yun Hee Rhee ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyp ◽  
Epithelial To Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Positive Control ◽  
Control Group ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
E Cadherin

BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.

E-cadherin and periostin in early detection and progression of diabetic nephropathy: epithelial-to-mesenchymal transition

2019 ◽  
Vol 23 (8) ◽  
pp. 1050-1057
Author(s):  
Nada M. Qamar El-Dawla ◽  
Al-Aliaa M. Sallam ◽  
Mohamed H. El-Hefnawy ◽  
Hala O. El-Mesallamy
Keyword(s):  
Diabetic Nephropathy ◽  
Early Detection ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
E Cadherin

Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats

Diabetes ◽  
1997 ◽  
Vol 46 (1) ◽  
pp. 94-106 ◽  
Author(s):  
J. R. Nyengaard ◽  
K. Chang ◽  
S. Berhorst ◽  
K. M. Reiser ◽  
J. R. Williamson ◽  
...  
Keyword(s):  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Structure And Function ◽  
Renal Structure ◽  
And Function

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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