Thromboxane A2 modulates the fibrinolytic system in glomerular mesangial cells.
We examined the effects of thromboxane A2 (TxA2) on the activities of the plasminogen-plasmin system in glomerular mesangial cells. When mesangial cells are exposed to the TxA2 agonist U-46619, a substantial increase in production of plasminogen activator inhibitor-1 (PAI-1) protein is observed that is significantly greater than that induced by 10% serum alone. This increase in PAI-1 protein production is accompanied by an increase in steady-state levels of PAI-1 mRNA. This stimulation is specifically mediated by TxA2 (thromboxane prostanoid, TP) receptors, since U-46619 also stimulates PAI-1 expression in cells that are transfected with TP receptors, and this stimulation of PAI-1 production is completely blocked by the TxA2 receptor antagonist, SQ-29,548. Despite the increase in PAI-1 production, there was net stimulation of plasmin activity in the medium of mesangial cells that had been exposed to U-46619. Furthermore, U-46619 also caused an increase in tissue plasminogen activator (tPA) mRNA levels. Thus TxA2 stimulates the production of PAI-1 and plasminogen activators by mesangial cells through a receptor-dependent mechanism. In inflammatory renal diseases, the balance of these effects may modulate glomerular thrombosis and renal fibrosis.
Coffman
T M
TM
Department of Medicine, Duke University and Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA.
Spurney
R F
RF
Mannon
R B
RB
Levenson
R
R
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000502:physiology*; D006834:Hydrazines / Q000494:pharmacology; D007700:Kinetics; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013928:Thromboxane A2 / Q000819:agonists / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin