Endothelin-1 induction of cyclooxygenase-2 expression in rat mesangial cells.
Prostaglandin E2 (PGE2) may be an important negative feedback modulator of endothelin-1 (ET-1)-stimulated mesangial cell proliferation and contraction. Recent studies suggest that ET-1 may induce prolonged mesangial cell PGE2 production, however the mechanism of this effect is unknown. The current study was undertaken, therefore, to examine the long-term effect of ET-1 on mesangial cell PGE2 synthesis. ET-1 markedly increased PGE2 release by rat mesangial cells for at least six hours. Cyclooxygenase (COX) activity was increased by one hour and persisted for at least six hours. ET-1 increased COX-2, but not COX-1, protein and mRNA levels. Actinomycin D reduced ET-1-stimulated PGE2 synthesis and COX-2 mRNA expression, while cycloheximide superinduced COX-2 mRNA. Dexamethasone decreased ET-1-stimulated PGE2 release and COX-2 protein and mRNA levels. ET-1-stimulated PGE2 release was prevented by BQ-123, an endothelin receptor A antagonist. We conclude that ET-1, via activation of the endothelin A receptor, causes a prolonged increase in mesangial cell PGE2 production that is partially dependent on induction of dexamethasone-inhibitable COX-2.
Hughes
A K
AK
Division of Nephrology, Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Padilla
E
E
Kutchera
W A
WA
Michael
J R
JR
Kohan
D E
DE
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism
D017931:DNA Primers; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D003907:Dexamethasone; D003513:Cycloheximide; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C072247:cyclo(Trp-Asp-Pro-Val-Leu)