scholarly journals Chrysin Ameliorates Cyclosporine-A-Induced Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial–Mesenchymal Transition

2021 ◽  
Vol 22 (19) ◽  
pp. 10252
Author(s):  
Rohan Reddy Nagavally ◽  
Siddharth Sunilkumar ◽  
Mumtaz Akhtar ◽  
Louis D. Trombetta ◽  
Sue M. Ford
Keyword(s):  
Proximal Tubule ◽  
Renal Dysfunction ◽  
Signaling Pathways ◽  
Cyclosporine A ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Proximal Tubule Cells ◽  
Mesenchymal Transition ◽  
Tubule Cells ◽  
Tgf Β1

Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial–mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells. Treatment with chrysin prevented CsA-induced renal dysfunction in Sprague Dawley rats measured by blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Chrysin inhibited CsA-induced tubulointerstitial fibrosis, characterized by reduced tubular damage and collagen deposition. In vitro, chrysin significantly inhibited EMT in LLC-PK1 cells, evidenced by inhibition of cell migration, decreased collagen expression, reduced presence of mesenchymal markers and elevated epithelial junction proteins. Furthermore, chrysin co-treatment diminished CsA-induced TGF-β1 signaling pathways, decreasing Smad 3 phosphorylation which lead to a subsequent reduction in Snail expression. Chrysin also inhibited activation of the Akt/ GSK-3β pathway. Inhibition of both pathways diminished the cytosolic accumulation of β-catenin, a known trigger for EMT. In conclusion, flavonoids such as chrysin offer protection against CsA-induced renal dysfunction and interstitial fibrosis. Chrysin was shown to inhibit CsA-induced TGF-β1-dependent EMT in proximal tubule cells by modulation of Smad-dependent and independent signaling pathways.

scholarly journals Role of Krüppel-like factor 6 in transforming growth factor-β1-induced epithelial-mesenchymal transition of proximal tubule cells

2008 ◽  
Vol 295 (5) ◽  
pp. F1388-F1396 ◽  
Author(s):  
John Holian ◽  
Weier Qi ◽  
Darren J. Kelly ◽  
Yuan Zhang ◽  
Ellein Mreich ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Proximal Tubule ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Proximal Tubule Cells ◽  
Mesenchymal Transition ◽  
Tubule Cells ◽  
Tgf Β1

Krüppel-like factor 6 (KLF6) is a DNA-binding protein containing a triple zinc-fingered motif and plays a key role in the regulation of cell proliferation, differentiation, and development. More recently it has been implicated in hepatic fibrosis via its binding to the transforming growth factor (TGF)-β control element. In the kidney, epithelial-mesenchymal transition (EMT) is a major contributor to the pathogenesis of renal fibrosis, with TGF-β1 being a key mediator of EMT. The present study aimed to determine the role of KLF6 and TGF-β1 in EMT in proximal tubule cells. To determine the relevance in clinical disease, KLF6 was measured in kidneys of streptozotocin-induced diabetic Ren-2 rats and in cells exposed to high (30 mM) glucose. TGF-β1 was confirmed to induce EMT by morphological change, loss of E-cadherin, and gain in vimentin expression. KLF6 mRNA expression was concomitantly measured. To determine the role of KLF6 in EMT, the above markers of EMT were determined in KLF6-silenced (small interfering RNA) and KLF6-overexpressing proximal tubule cells. KLF6 overexpression significantly promoted a phenotype consistent with EMT. High glucose induced KLF6 in proximal tubule cells ( P < 0.05). This increase in KLF6 in response to high glucose was TGF-β1 mediated. In an in vivo model of diabetic nephropathy KLF6 increased at week 8 ( P < 0.05). KLF6 plays a permissive role in TGF-β1-induced EMT in proximal tubule cells. Its upregulation in in vivo models of diabetic nephropathy suggests it as a potential therapeutic target.

scholarly journals Signaling pathways utilized by PTH and dopamine to inhibit phosphate transport in mouse renal proximal tubule cells

2009 ◽  
Vol 296 (2) ◽  
pp. F355-F361 ◽  
Author(s):  
Rochelle Cunningham ◽  
Rajatsubhra Biswas ◽  
Marc Brazie ◽  
Deborah Steplock ◽  
Shirish Shenolikar ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Signaling Pathways ◽  
Phosphate Transport ◽  
Inhibitory Effect ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Phosphate Cotransport ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
Sodium Phosphate Cotransport

The present experiments were designed to detail factors regulating phosphate transport in cultured mouse proximal tubule cells by determining the response to parathyroid hormone (PTH), dopamine, and second messenger agonists and inhibitors. Both PTH and dopamine inhibited phosphate transport by over 30%. The inhibitory effect of PTH was completely abolished in the presence of chelerythrine, a PKC inhibitor, but not by Rp-cAMP, a PKA inhibitor. By contrast, both chelerythrine and Rp-cAMP blocked the inhibitory effect of dopamine. Chelerythrine inhibited PTH-mediated cAMP accumulation but also blocked the inhibitory effect of 8-bromo-cAMP on phosphate transport. On the other hand, Rp-cAMP had no effect on the ability of DOG, a PKC activator, to inhibit phosphate transport. PD98059, an inhibitor of MAPK, had no effect on PTH- or dopamine-mediated inhibition of sodium-phosphate cotransport. Finally, compared with 8-bromo-cAMP, 8-pCPT-2′- O-Me-cAMP, an activator of EPAC, had no effect on phosphate transport. These results outline significant differences in the signaling pathways utilized by PTH and dopamine to inhibit renal phosphate transport. Our results also suggest that activation of MAPK is not critically involved in PTH- or dopamine-mediated inhibition of phosphate transport in mouse renal proximal tubule cells in culture.

Interleukin-6 stimulates α-MG uptake in renal proximal tubule cells: involvement of STAT3, PI3K/Akt, MAPKs, and NF-κB

2007 ◽  
Vol 293 (4) ◽  
pp. F1036-F1046 ◽  
Author(s):  
Yu Jin Lee ◽  
Jung Sun Heo ◽  
Han Na Suh ◽  
Min Young Lee ◽  
Ho Jae Han
Keyword(s):  
Protein Expression ◽  
Proximal Tubule ◽  
Signaling Pathways ◽  
Interleukin 6 ◽  
Renal Proximal Tubule ◽  
Expression Level ◽  
Protein Expression Level ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells

Recent studies have shown that interleukin 6 (IL-6) acts on the cellular proliferation-activating transduction signals during cellular regeneration. Therefore, this study examined the effect of IL-6 on the activation of Na+/glucose cotransporters (SGLTs) and its related signaling pathways in primary cultured renal proximal tubule cells (PTCs). IL-6 increased the level of α-methyl-d-[14C]glucopyranoside (α-MG) uptake in time- and dose-dependent manners. IL-6 also increased SGLT1 plus SGLT2 mRNA and protein expression level. The IL-6 receptors (IL-6Rα and gp130) were expressed in PTCs. In addition, genistein and herbimycin A completely blocked the IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs. On the other hand, IL-6 increased the level of 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate-sensitive cellular reactive oxygen species (ROS), and IL-6-induced increases in α-MG uptake and the protein expression level of SGLTs were blocked by ascorbic acid or taurine (antioxidants). IL-6 also increased the phosphorylation of signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) in a time-dependent manner. A pretreatment with STAT3 inhibitor LY 294002, an Akt inhibitor, or MAPK inhibitors significantly blocked the IL-6-induced increase in α-MG uptake. In addition, IL-6 increased the level of nuclear factor-κB (NF-κB) phosphorylation. A pretreatment with SN50 or BAY 11-7082 also blocked the IL-6-induced increase in α-MG uptake. In conclusion, IL-6 increases the SGLT activity through ROS, and its action in renal PTCs is associated with the STAT3, PI3K/Akt, MAPKs, and NF-κB signaling pathways.

Klotho mitigates cyclosporine A (CsA)-induced epithelial–mesenchymal transition (EMT) and renal fibrosis in rats

2016 ◽  
Vol 49 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Qi-feng Liu ◽  
Jian-ming Ye ◽  
Li-xia Yu ◽  
Xiao-hong Dong ◽  
Jian-hua Feng ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

Signaling pathways involved in the rapid biphasic effect of aldosterone on Na + /H + exchanger in rat proximal tubule cells

2018 ◽  
Vol 182 ◽  
pp. 87-94 ◽  
Author(s):  
Deise C.A. Leite-Dellova ◽  
Shirley J. Szriber ◽  
Giovana K.F. Merighe ◽  
Juliano Z. Polidoro ◽  
Nancy A. Rebouças ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Signaling Pathways ◽  
Proximal Tubule Cells ◽  
Biphasic Effect ◽  
Tubule Cells ◽  
Rat Proximal Tubule

scholarly journals Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Zhen-feng Hou ◽  
Hao-yue Zhu ◽  
Xiao-xuan Chen ◽  
Wan-yang Li ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Gene Expression Omnibus ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Collagen Remodeling ◽  
Gsk 3Β ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

scholarly journals IL-1β augments TGF-β inducing epithelial-mesenchymal transition of epithelial cells and associates with poor pulmonary function improvement in neutrophilic asthmatics

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shengding Zhang ◽  
Yu Fan ◽  
Lu Qin ◽  
Xiaoyu Fang ◽  
Cong Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Epithelial Mesenchymal Transition ◽  
Inhaled Corticosteroids ◽  
A549 Cells ◽  
Mapk Signaling ◽  
Basement Membranes ◽  
Healthy Controls ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Methods Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. Results NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1 compared to EA. For all asthmatics, sputum IL-1β mRNA was positively correlated with protein expression. Sputum IL-1β mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1β mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1β augmenting TGF-β1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. Conclusions IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways. Trial registration: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).

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