Reactive oxygen species, PKC-β1, and PKC-ζ mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells

2007 ◽  
Vol 293 (5) ◽  
pp. E1280-E1288 ◽  
Author(s):  
Ling Xia ◽  
Hong Wang ◽  
Snezana Munk ◽  
Helena Frecker ◽  
Howard J. Goldberg ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Endothelial Growth Factor ◽  
High Glucose ◽  
Mesangial Cells ◽  
Vascular Endothelial ◽  
Oxygen Species ◽  
Vegf Expression ◽  
Pkc Β ◽  
Pkc Ζ ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is implicated in the development of proteinuria in diabetic nephropathy. High ambient glucose present in diabetes stimulates VEGF expression in several cell types, but the molecular mechanisms are incompletely understood. Here primary cultured rat mesangial cells served as a model to investigate the signal transduction pathways involved in high-glucose-induced VEGF expression. Exposure to high glucose (25 mM) significantly increased VEGF mRNA evaluated by real-time PCR by 3 h, VEGF cellular protein content assessed by immunoblotting or immunofluorescence within 24 h, and VEGF secretion by 24 h. High-glucose-induced VEGF expression was blocked by an antioxidant, Tempol, and antisense oligonucleotides directed against p22phox, a NADPH oxidase subunit. Inhibition of protein kinase C (PKC)-β1 with the specific pharmacological inhibitor LY-333531 or inhibition of PKC-ζ with a cell permeable specific pseudosubstrate peptide also prevented enhanced VEGF expression in high glucose. Enhanced VEGF secretion in high glucose was prevented by Tempol, PKC-β1, or PKC-ζ inhibition. In normal glucose (5.6 mM), overexpression of p22phox or constitutively active PKC-ζ enhanced VEGF expression. Hypoxia inducible factor-1α protein was significantly increased in high glucose only by 24 h, suggesting a possible contribution to high-glucose-stimulated VEGF expression at later time points. Thus reactive oxygen species generated by NADPH oxidase, and both PKC-β1 and -ζ, play important roles in high-glucose-stimulated VEGF expression and secretion by mesangial cells.

scholarly journals Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells

2000 ◽  
Vol 165 (3) ◽  
pp. 617-624 ◽  
Author(s):  
NH Kim ◽  
HH Jung ◽  
DR Cha ◽  
DS Choi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
High Glucose ◽  
Mesangial Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Protein Levels ◽  
Calphostin C ◽  
Endothelial Growth Factor

Diabetic nephropathy associated with hyperglycemia is characterized by glomerular hyperfiltration and endothelial dysfunction. Vascular endothelial growth factor (VEGF) is known to be primarily involved in neoangiogenesis and increased endothelial permeability. The purpose of this study was to investigate VEGF expression in response to high glucose in rat cultured mesangial cells and to identify its signal pathway via protein kinase C (PKC). Rat mesangial cells were cultured with different concentrations of glucose: normal (5 mM d-glucose), medium (15 mM d-glucose) and high (30 mm d-glucose). Calphostin-C as a PKC inhibitor and phorbol myristate acetate (PMA) as a PKC downregulator were instillated into culture media to evaluate the role of PKC in mediating the glucose-induced increase in VEGF expression. High glucose increased expression of VEGF at the mRNA and protein levels, identified by semi-quantitative RT-PCR and western blotting, within 3 h and in a time- and glucose concentration-dependent manner. Calphostin-C and PMA inhibited glucose-induced increases in VEGF expression at the mRNA and protein levels. In conclusion, high glucose can directly increase VEGF expression in rat mesangial cells via a PKC-dependent mechanism. These results suggest that VEGF could be a potential mediator of glomerular hyperfiltration and proteinuria in diabetic nephropathy.

scholarly journals Rosiglitazone Prevents High Glucose-Induced Vascular Endothelial Growth Factor and Collagen IV Expression in Cultured Mesangial Cells

2009 ◽  
Vol 2009 ◽  
pp. 1-11 ◽  
Author(s):  
Catharine Whiteside ◽  
Hong Wang ◽  
Ling Xia ◽  
Snezana Munk ◽  
Howard J. Goldberg ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
High Glucose ◽  
Mesangial Cells ◽  
Collagen Iv ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Peroxisome proliferator-activated receptor (PPARγ), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPARγprevents the upregulation of vascular endothelial growth factor (VEGF) and collagen IV by mesangial cells exposed to high glucose. Primary cultured rat mesangial cells were growth-arrested in 5.6 mM (NG) or 25 mM D-glucose (HG) for up to 48 hours. In HG, PPARγmRNA and protein were reduced within 3 h, and enhanced ROS generation, expression ofp22phox, VEGF and collagen IV, and PKC-ζmembrane association were prevented by RSG. In NG, inhibition of PPARγcaused ROS generation and VEGF expression that were unchanged by RSG. Reduced AMP-activated protein kinase (AMPK) phosphorylation in HG was unchanged with RSG, and VEGF expression was unaffected by AMPK inhibition. Hence, PPARγis a negative modulator of HG-induced signaling that acts through PKC-ζbut not AMPK and regulates VEGF and collagen IV expression by mesangial cells.

scholarly journals Retinoic Acid Is a Cofactor for Translational Regulation of Vascular Endothelial Growth Factor in Human Endometrial Stromal Cells

2010 ◽  
Vol 24 (1) ◽  
pp. 148-160 ◽  
Author(s):  
Neil Sidell ◽  
Yue Feng ◽  
Lijuan Hao ◽  
Juanjuan Wu ◽  
Jie Yu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Endothelial Growth Factor ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Stromal Cells ◽  
Vascular Endothelial ◽  
Oxygen Species ◽  
Transcriptional Activators ◽  
Endometrial Stromal Cells ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-β; and IL-1β). Whereas TPA or TGF-β alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.

scholarly journals Roles of Reactive Oxygen Species in Anticancer Therapy withSalvia miltiorrhiza Bunge

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Yu-Chiang Hung ◽  
Tai-Long Pan ◽  
Wen-Long Hu
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Anticancer Therapy ◽  
Vascular Endothelial ◽  
Oxygen Species ◽  
Endothelial Growth Factor

Cancer is a leading cause of death worldwide. We aim to provide a systematic review about the roles of reactive oxygen species (ROS) in anticancer therapy withSalvia miltiorrhizaBunge (Danshen). Danshen, including its lipophilic and hydrophilic constituents, is potentially beneficial for treating various cancers. The mechanisms of ROS-related anticancer effects of Danshen vary depending on the specific type of cancer cells involved. Danshen may enhance TNF-α-induced apoptosis, upregulate caspase-3, caspase-8, caspase-9, endoplasmic reticulum stress, P21, P53, Bax/Bcl-2, DR5, and AMP-activated protein kinase, or activate the p38/JNK, mitogen-activated protein kinase, and FasL signaling pathways. Conversely, Danshen may downregulate human telomerase reverse transcriptase mRNA, telomerase, survivin, vascular endothelial growth factor/vascular endothelial growth factor receptor 2, CD31, NF-κB, Erk1/2, matrix metalloproteinases, microtubule assembly, and receptor tyrosine kinases including epidermal growth factor receptors, HER2, and P-glycoprotein and inhibit the PI3K/Akt/mTOR or estrogen receptor signaling pathways. Therefore, Danshen may inhibit cancer cells proliferation through antioxidation on tumor initiation and induce apoptosis or autophagy through ROS generation on tumor progression, tumor promotion, and tumor metastasis. Based on the available evidence regarding its anticancer properties, this review provides new insights for further anticancer research or clinical trials with Danshen.

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