Thromboxane and prostacyclin differentially regulate murine extracellular matrix gene expression.
Alterations in the arachidonic acid metabolites thromboxane and prostacyclin are known to contribute to hemodynamic changes observed in certain models of acute and chronic renal failure. We have previously shown that thromboxane may have an important role in mediating glomerulosclerosis by stimulating the expression of certain extracellular matrix proteins. In the present study, we compared the effects of thromboxane and prostacyclin on the expression of genes encoding basement membrane proteins using a murine teratocarcinoma cell line, that when differentiated to an endodermal phenotype synthesizes abundant extracellular matrix. Incubation of these cells with stable analogs of thromboxane and prostacyclin for four hours resulted in changes in basement membrane gene expression. Thromboxane increased steady-state mRNA levels for all three laminin chains, type IV collagen, and fibronectin, but decreased the level of mRNA for heparan sulfate proteoglycan. In contrast, incubation with carbo-prostacyclin, a stable analog of prostacyclin, decreased the steady-state mRNA level for the laminin A and B1 chains, type IV collagen and fibronectin, and increased the mRNA level for heparan sulfate proteoglycan and laminin B2. Carbo-prostacyclin did not affect cellular proliferation or thymidine incorporation. These results indicate that eicosanoids directly modulate matrix gene expression independently of hemodynamic influence, and independently of effects mediated by platelets, or mitogenesis. Furthermore, these findings suggest that the alterations in renal eicosanoid metabolism may directly participate in the pathogenesis of glomerulosclerosis and thus provide a rationale for therapy directed toward the specific inhibition of thromboxane in the treatment of progressive glomerular sclerosis.
Bruggeman
L A
LA
Molecular Medicine Section, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland.
Pellicoro
J A
JA
Horigan
E A
EA
Klotman
P E
PE
D000818:Animals; D003094:Collagen / Q000235:genetics; D011464:Epoprostenol / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000235:genetics; D007797:Laminin / Q000235:genetics; D051379:Mice; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013928:Thromboxane A2 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D003094:Collagen; D011464:Epoprostenol; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D013928:Thromboxane A2