Quercetin inhibits the amphiregulin/<scp>EGFR</scp> signaling‐mediated renal tubular epithelial‐mesenchymal transition and renal fibrosis in obstructive nephropathy

Wang, Qi; Wang, Fuqiang; Li, Xiangze; Ma, Zhi; Jiang, Dapeng

doi:10.1002/ptr.7599

Cited by 10 publications

(2 citation statements)

References 46 publications

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“…As shown in Figure1A,B, vimentin expression was significantly upregulated after 48 h of TGFβ1 stimulation. This result is consistent with that reported in several studies, indicating the occurrence of EMT in HK-2 cells upon TGFβ1 stimulation [27][28][29]. Of note, the expression of vimentin phosphorylation at Ser72 was significantly increased after TGFβ1 stimulation, suggesting its potential role in EMT progression of HK-2 cells.…”

supporting

confidence: 92%

Phosphorylated vimentin at Ser72 is associated with epithelial–mesenchymal transition in lupus nephritis

Wang,

Zhang,

et al. 2023

Int J of Rheum Dis

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ObjectivesTo measure the expression of vimentin and its phosphorylated forms in lupus nephritis (LN) and explore their potential role in LN development.MethodsLupus renal biopsies from LN patients and normal renal biopsies from kidney transplant donors were collected. The expression of vimentin and its phosphorylated forms (p‐vimentin (Ser39, Ser56, Ser72, Ser83, and Tyr117)) were measured by Western blots and immunohistochemistry. To construct stable cell line that overexpress vimentin and its phosphorylated forms, an immortalized proximal tubule epithelial cell line (HK‐2 cells) was utilized. The roles of vimentin and its phosphorylated forms on the migration of HK‐2 cells were examined by transwell migration assay and wound healing analysis.ResultsWe first observed a significant upregulation of vimentin protein in TGFβ1‐induced HK‐2 cells. This finding was further confirmed in renal tissues obtained from LN patients and animal model. Interestingly, among the five phosphorylated forms of vimentin, only vimentin phosphorylated at Ser72 was upregulated in LN. Through the establishment of stable vimentin and its phosphorylated forms overexpression in HK‐2 cells, we found that the overexpression of vimentin and its phosphorylated forms at Ser72 significantly enhances the cell migration.ConclusionsVimentin phosphorylated on Ser72 is important for renal epithelial cell migration, which would enhance the progression of vimentin‐induced epithelial–mesenchymal transition during LN development.

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confidence: 92%

Phosphorylated vimentin at Ser72 is associated with epithelial–mesenchymal transition in lupus nephritis

Wang,

Zhang,

et al. 2023

Int J of Rheum Dis

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“…EGFR inhibitors may reduce DKD by reducing ROS and ER stress. Quercetin can reduce renal fibrosis in vitro and in vivo by inhibiting EGFR signaling activation[ 44 , 45 ]. TNF may serve as an autonomous risk factor for the development of chronic kidney disease in patients diagnosed with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease

Zhang,

Zheng

2024

World J Diabetes

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BACKGROUND Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. The Astragalus -Coptis drug pair is frequently employed in the management of DKD. However, the precise molecular mechanism underlying its therapeutic effect remains elusive. AIM To investigate the synergistic effects of multiple active ingredients in the Astragalus-Coptis drug pair on DKD through multiple targets and pathways. METHODS The ingredients of the Astragalus -Coptis drug pair were collected and screened using the TCMSP database and the SwissADME platform. The targets were predicted using the SwissTargetPrediction database, while the DKD differential gene expression analysis was obtained from the Gene Expression Omnibus database. DKD targets were acquired from the GeneCards, Online Mendelian Inheritance in Man database, and DisGeNET databases, with common targets identified through the Venny platform. The protein-protein interaction network and the “disease-active ingredient-target” network of the common targets were constructed utilizing the STRING database and Cytoscape software, followed by the analysis of the interaction relationships and further screening of key targets and core active ingredients. Gene Ontology (GO) function and Kyoto Ency-clopedia of Genes and Genomes (KEGG) pathway enrichments were performed using the DAVID database. The tissue and organ distributions of key targets were evaluated. PyMOL and AutoDock software validate the molecular docking between the core ingredients and key targets. Finally, molecular dynamics (MD) simulations were conducted to simulate the optimal complex formed by interactions between core ingredients and key target proteins. RESULTS A total of 27 active ingredients and 512 potential targets of the Astragalus -Coptis drug pair were identified. There were 273 common targets between DKD and the Astragalus -Coptis drug pair. Through protein-protein interaction network topology analysis, we identified 9 core active ingredients and 10 key targets. GO and KEGG pathway enrichment analyses revealed that Astragalus -Coptis drug pair treatment for DKD involves various biological processes, including protein phosphorylation, negative regulation of apoptosis, inflammatory response, and endoplasmic reticulum unfolded protein response. These pathways are mainly associated with the advanced glycation end products (AGE)-receptor for AGE products signaling pathway in diabetic complications, as well as the Lipid and atherosclerosis. Molecular docking and MD simulations demonstrated high affinity and stability between the core active ingredients and key targets. Notably, the quercetin-AKT serine/threonine kinase 1 (AKT1) and quercetin-tumor necrosis factor (TNF) protein complexes exhibited exceptional stability. CONCLUSION This study demonstrated that DKD treatment with the Astragalus -Coptis drug pair involves multiple ingredients, targets, and signaling pathways. We propose a novel approach for investigating the molecular mechanism underlying the therapeutic effects of the Astragalus -Coptis drug pair on DKD. Furthermore, we suggest that quercetin is the most potent active ingredient and specifically targets AKT1 and TNF, providing a theoretical foundation for further exploration of pharmacologically active ingredients and elucidating their molecular mechanisms in DKD treatment.

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Epithelial–mesenchymal plasticity in kidney fibrosis

Hadpech

Thongboonkerd

2023

Genesis

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SummaryEpithelial–mesenchymal transition (EMT) is an important biological process contributing to kidney fibrosis and chronic kidney disease. This process is characterized by decreased epithelial phenotypes/markers and increased mesenchymal phenotypes/markers. Tubular epithelial cells (TECs) are commonly susceptible to EMT by various stimuli, for example, transforming growth factor‐β (TGF‐β), cellular communication network factor 2, angiotensin‐II, fibroblast growth factor‐2, oncostatin M, matrix metalloproteinase‐2, tissue plasminogen activator (t‐PA), plasmin, interleukin‐1β, and reactive oxygen species. Similarly, glomerular podocytes can undergo EMT via these stimuli and by high glucose condition in diabetic kidney disease. EMT of TECs and podocytes leads to tubulointerstitial fibrosis and glomerulosclerosis, respectively. Signaling pathways involved in EMT‐mediated kidney fibrosis are diverse and complex. TGF‐β1/Smad and Wnt/β‐catenin pathways are the major venues triggering EMT in TECs and podocytes. These two pathways thus serve as the major therapeutic targets against EMT‐mediated kidney fibrosis. To date, a number of EMT inhibitors have been identified and characterized. As expected, the majority of these EMT inhibitors affect TGF‐β1/Smad and Wnt/β‐catenin pathways. In addition to kidney fibrosis, these EMT‐targeted antifibrotic inhibitors are expected to be effective for treatment against fibrosis in other organs/tissues.

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Quercetin inhibits the amphiregulin/EGFR signaling‐mediated renal tubular epithelial‐mesenchymal transition and renal fibrosis in obstructive nephropathy

Cited by 10 publications

References 46 publications

Phosphorylated vimentin at Ser72 is associated with epithelial–mesenchymal transition in lupus nephritis

Phosphorylated vimentin at Ser72 is associated with epithelial–mesenchymal transition in lupus nephritis

Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease

Epithelial–mesenchymal plasticity in kidney fibrosis

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