Cyclooxygenase-derived metabolites of 8,9-epoxyeicosatrienoic acid are potent mitogens for cultured rat glomerular mesangial cells.
The mitogenic effects of 11(R)-hydroxy-8,9-epoxyeicosatrienoic acid (EET) enantiomers were investigated in cultured rat glomerular mesangial cells. Both 11(R)-hydroxylated 8(R),9(S)- and 8(S),9(R)-EET at 1 microM stimulated [3H]-thymidine incorporation to 300% and 280%, with 50% maximal effect occurring at 8 x 10(-9) M and 1 x 10(-8) M, respectively. Similar concentration-dependent effects were observed in stimulating induction of the immediate early gene, c-fos. Mitogenic activity of the 11(R)-hydroxylated enantiomers was not affected by prior downregulation of protein kinase C, suggesting involvement of protein kinase C-independent mechanisms. These findings suggest that either trans- or intracellular metabolism of 8,9-EET by cyclooxygenase occurs during inflammatory glomerular diseases and that the resulting metabolites are involved in mesangial cell proliferation.
Homma
T
T
Department of Pediatrics, Vanderbilt University, Nashville, TN.
Zhang
J Y
JY
Shimizu
T
T
Prakash
C
C
Blair
I A
IA
Harris
R C
RC
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000199:Actins / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016762:Genes, fos / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008934:Mitogens / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013237:Stereoisomerism; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D000199:Actins; D008934:Mitogens; D012333:RNA, Messenger; D014316:Tritium; C080015:11-hydroxy-8,9-epoxyeicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D015126:8,11,14-Eicosatrienoic Acid; D013936:Thymidine