Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells.
Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells.


BACKGROUND
Vascular endothelial growth factor (VEGF) is an endothelial mitogen that is constitutively expressed in normal human glomeruli, but its role in the kidney is still unclear. In this study, we examined the effects of VEGF on human mesangial cells (HMCs). Methods and Results. Reverse transcription-polymerase chain reaction analysis demonstrated the presence of VEGF receptor mRNA (flt-1 and KDR) in HMCs. The treatment of HMCs with VEGF did not cause a change in 3H-thymidine incorporation or cell numbers. In contrast, VEGF caused a dose- and time-dependent increase in collagen synthesis, with threefold to fivefold increases in both cell-associated and secreted collagen synthesis seen after treatment with 200 ng/ml VEGF. The effects of VEGF were attenuated by treatment of HMCs with the tyrosine kinase inhibitor herbimycin A or the MEK inhibitor PD 98059, but not with the protein kinase C (PKC) inhibitor chelerythrine. VEGF treatment also caused a marked increase in p42/p44 mitogen-activated protein kinase (MAPK) activity, but had no significant effect on HMC superoxide production. Finally, an increase in collagen synthesis was also seen in rat mesangial cells treated with VEGF.


CONCLUSIONS
These results suggest that VEGF is not a mitogenic signal in HMCs, but may be involved in the regulation of the mesangial matrix in humans by a MAPK-dependent mechanism.
Amemiya
T
T
Departmnet of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Sasamura
H
H
Mifune
M
M
Kitamura
Y
Y
Hirahashi
J
J
Hayashi
M
M
Saruta
T
T
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005920:Glomerular Mesangium / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D008222:Lymphokines / Q000235:genetics* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011347:Procollagen / Q000378:metabolism; D011493:Protein Kinase C / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C042813:procollagen type I carboxy terminal peptide; D013481:Superoxides; D014443:Tyrosine; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases