Eicosapentaenoic acid inhibits PDGF-induced mitogenesis and cyclin D1 expression via TGF-beta in mesangial cells.
Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid derived from fish oil, is efficacious in glomerular diseases where mesangial proliferation is a key event. We examined the mechanisms of action of EPA on platelet-derived growth factor (PDGF)-stimulated rat mesangial cell mitogenesis. EPA dose-dependently inhibited PDGF-stimulated [(3)H]-thymidine incorporation. PDGF-induced PDGF receptor autophosphorylation, an initial event for PDGF signaling, was not affected by 2 micro g/ml EPA. Similarly, PDGF-stimulated activation of extracellular signal-regulated kinase (ERK) was not altered. On the other hand, EPA inhibited cyclin-dependent kinase 4 (CDK4) activation and cyclin D1 protein induction, a critical step for G1/S progression. TGF-beta secretion assessed by ELISA and bioassay was increased by EPA at 18 h. Coincubation with anti-TGF-beta antibody inhibited the EPA-induced suppression of [(3)H]-thymidine incorporation and cyclin D1 expression. SB203580, an inhibitor of p38, a downstream kinase of TGF-beta, did not affect EPA's growth inhibitory effect. These results demonstrate that EPA inhibits PDGF-stimulated mesangial cell mitogenesis and cyclin D1 expression via TGF-beta.
Hida
Mariko
M
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Fujita
Hisayo
H
Ishikura
Kenji
K
Omori
Sayu
S
Hoshiya
Makiko
M
Awazu
Midori
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D015118:Eicosapentaenoic Acid; D017479:Receptors, Platelet-Derived Growth Factor; C495900:CDK4 protein, human; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; D013936:Thymidine