scholarly journals Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells

1999 ◽  
Vol 338 (2) ◽  
pp. 367-374 ◽  
Author(s):  
Stefan FRANK ◽  
Birgit STALLMEYER ◽  
Heiko KÄMPFER ◽  
Christian SCHAFFNER ◽  
Josef PFEILSCHIFTER
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Mesangial Cells ◽  
Differential Regulation ◽  
Moderate Increase ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Under conditions associated with local and systemic inflammation, mesangial cells and invading immune cells are likely to be responsible for the release of large amounts of nitric oxide (NO) in the glomerulus. To further define the mechanisms of NO action in the glomerulus, we attempted to identify genes which are regulated by NO in rat glomerular mesangial cells. We identified vascular endothelial growth factor (VEGF) and its receptor fms-like tyrosine kinase (FLT-1) to be under the regulatory control of exogenously applied NO in these cells. Using S-nitroso-glutathione (GSNO) as an NO-donating agent, VEGF expression was strongly induced, whereas expression of its FLT-1 receptor simultaneously decreased. Expressional regulation of VEGF and FLT-1 mRNA was transient and occurred rapidly within 1–3 h after GSNO treatment. Expression of a second VEGF-specific receptor, fetal liver kinase-1 (FLK-1/KDR), could not be detected. The inflammatory cytokine interleukin-1β mediated a moderate increase in VEGF expression after 24 h and had no influence on FLT-1 expression. In contrast, platelet-derived growth factor–BB and basic fibroblast growth factor had no effect on VEGF expression, but strongly induced FLT-1 mRNA levels. Obviously, there is a differential regulation of VEGF and its receptor FLT-1 by NO, cytokines and growth factors in rat 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.

Regulation of Vascular Endothelial Growth Factor Gene Expression in Murine Macrophages by Nitric Oxide and Hypoxia

2003 ◽  
Vol 228 (6) ◽  
pp. 697-705 ◽  
Author(s):  
Madhuri Ramanathan ◽  
Avi Giladi ◽  
S. Joseph Leibovich
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cell Density ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Ifn Γ ◽  
Cell Densities ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Vascular endothelial growth factor (VEGF) expression in murine peritoneal macrophages is strongly upregulated by hypoxia via transcriptional and posttranscriptional mechanisms. Interferon-γ (IFN-γ) with Escherichia coll lipopolysaccharide (LPS) also upregulates expression of VEGF, as well as of the inducible nitric oxide synthase (INOS). Hypoxia (1% O2) upregulates VEGF expression in macrophages from both wild-type and INOS knockout mice, indicating that hypoxic upregulation of VEGF is independent of INOS. However, the INOS inhibitor aminoguanidine (AG) decreases the VEGF expression induced by LPS/IFN-γ, indicating an important role for NO. NO-dependent induction of VEGF is strongly dependent on cell density. LPS/IFN-γ treatment induces minimal VEGF protein expression in macrophages cultured at low cell densities (<0.25 × 106 cells/cm2); at higher cell densities (>0.25 × 106 cells/cm2) that lead to conditions of pericellular hypoxia, however, induction of VEGF expression was strong. Transient transfection of RAW 264.7 cells with luciferase reporter constructs of the murine VEGF promoter indicates that both hypoxia and LPS/IFN-γ independently induce VEGF promoter activity, irrespective of cell density. Although LPS/IFN-γ treatment induces transcriptional activation of the VEGF promoter, significant levels of VEGF protein are only expressed by cells at high density under conditions of pericellular hypoxia. This suggests an important regulatory role for hypoxia at the posttranscriptional level. Deletion analysis of the VEGF promoter shows that the hypoxia response element region and its immediate flanking sequences are essential for both hypoxia and LPS/IFN-γ-induced VEGF promoter activation.

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.

Upregulation of angiotensin-converting enzyme by vascular endothelial growth factor

2001 ◽  
Vol 280 (2) ◽  
pp. H885-H891 ◽  
Author(s):  
Outi Saijonmaa ◽  
Tuulikki Nyman ◽  
Riikka Kosonen ◽  
Frej Fyhrquist
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Angiotensin Converting Enzyme ◽  
Tyrosine Kinase ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Converting Enzyme ◽  
Endothelial Growth Factor

The role of vascular endothelial growth factor (VEGF), a potent endothelium-specific angiogenic factor, in the regulation of angiotensin-converting enzyme (ACE) in cultured human umbilical vein endothelial cells (HUVECs) was studied. VEGF (0.07–1.2 × 10−6mmol/l) caused a dose-dependent increase in ACE measured in intact endothelial cells and increased the expression of ACE mRNA. The stimulatory effect of VEGF was inhibited by pretreatment of endothelial cells with the tyrosine kinase inhibitor herbimycin (4.35 × 10−5mmol/l). The stimulatory effect of VEGF was potentiated by the selective cGMP phosphodiesterase inhibitor zaprinast (0.1 mmol/l). The nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME; 5.4 mmol/l) suppressed the stimulatory effect of VEGF. The nonselective cyclooxygenase (COX) inhibitor indomethacin (5 μM) and the selective COX-2 inhibitor NS-398 (5 μM) potentiated the stimulatory effect of VEGF, whereas the selective COX-1 inhibitor resveratrol (5 μM) was without effect. ACE induction by VEGF was inhibited by the selective protein kinase C (PKC) inhibitor GF109203X (2.5 × 10−3mmol/l) and by downregulating PKC with phorbol 12-myristate 13-acetate. In summary, VEGF induced ACE in cultured HUVECs. Intracellular events such as tyrosine kinase activation, PKC activation, and increase of cGMP were probably involved in ACE induction by VEGF. Nitric oxide may partially contribute to ACE induction by VEGF. The powerful capacity of VEGF to increase ACE in endothelial cells shown here suggests a synergistic relation between VEGF and the renin-angiotensin system in vascular biology and pathophysiology.

scholarly journals Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis.

2003 ◽  
Vol 50 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Hideo Kimura ◽  
Hiroyasu Esumi
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Physiologically, angiogenesis is tightly regulated, or otherwise it leads to pathological processes, such as tumors, inflammatory diseases, gynecological diseases and diabetic retinopathy. The vascular endothelial growth factor (VEGF) is a potent and critical inducer of angiogenesis. The VEGF gene expression is regulated by a variety of stimuli. Hypoxia is one of the most potent inducers of the VEGF expression. The hypoxia inducible factor 1 (HIF-1) plays as a key transcription factor in hypoxia-mediated VEGF gene upregulation. Nitric oxide (NO) as well as hypoxia is reported to upregulate the VEGF gene by enhancing HIF-1 activity. The Akt/protein kinase B (PKB) pathway may be involved in NO-mediated HIF-1 activation in limited cell lines. There are some reports of negative effects of NO on HIF-1 and VEGF activity. These conflicting data of NO effects may be attributed mainly to the amount of released NO. Indeed, NO can be a positive or negative modulator of the VEGF gene under the same conditions simply by changing its amounts. The VEGF-mediated angiogenesis requires NO production from activated endothelial NO synthase (eNOS). Activation of eNOS by VEGF involves several pathways including Akt/PKB, Ca(2+)/calmodulin, and protein kinase C. The NO-mediated VEGF expression can be regulated by HIF-1 and heme oxygenase 1 (HO-1) activity, and the VEGF-mediated NO production by eNOS can be also modulated by HIF-1 and HO-1 activity, depending upon the amount of produced NO. These reciprocal relations between NO and VEGF may contribute to regulated angiogenesis in normal tissues.

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