PGE2 reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop.
Increased glomerular prostaglandin E(2) (PGE(2)) production is associated with the progression of diseases such as membranous nephropathy, nephrotic syndrome, and anti-Thy1 nephritis. We investigated the signaling pathways that regulate the synthesis and actions of PGE(2) in glomerular podocytes. To study its actions, we assessed the ability of PGE(2) to regulate the production of its own precursor, arachidonic acid (AA), in a mouse podocyte cell line. PGE(2) dose-dependently reduced phorbol ester (PMA)-mediated AA release. Inhibition of PMA-stimulated AA release by PGE(2) was found to be cAMP/PKA-dependent, because PGE(2) significantly increased levels of this second messenger, whereas the inhibitory actions of PGE(2) were reversed by PKA inhibition and reproduced by the cAMP-elevating agents forskolin and IBMX. PGE(2) synthesis in this podocyte cell line increased fourfold at 60 min in response to PMA, coinciding with upregulation of cyclooxygenase (COX)-2 but not COX-1 levels. However, PGE(2) synthesis was significantly reduced by COX-1-selective inhibition, yet to a lesser extent by COX-2-selective inhibition. Our findings suggest that PMA-stimulated PGE(2) synthesis in mouse podocytes requires both basal COX-1 activity and induced COX-2 expression, and that PGE(2) reduces PMA-stimulated AA release in a cAMP/PKA-dependent manner. Such an autocrine regulatory loop might have important consequences for podocyte and glomerular function in the context of renal diseases involving PGE(2) synthesis.
Lemieux
Lyne I
LI
Division of Nephrology, Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Rahal
Sherine S
SS
Kennedy
Chris R J
CR
D000818:Animals; D016824:Antigens, Human Platelet / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016824:Antigens, Human Platelet; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; C083451:human platelet antigen 1b; D016718:Arachidonic Acid; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate