Previous studies have demonstrated that thromboxane (TX) stimulates matrix protein synthesis in mesangial cells (MC), and that this action is signalled by receptor mediated activation of protein kinase C (PKC). In the present study, we examined the hypothesis that activation of PKC by TX signals increases in transforming growth factor beta (TGF-beta) bioactivity, which in turn induces enhanced matrix protein synthesis. In cultured rat MC, the TXA2/prostaglandin endoperoxide analogue U-46619, but not exogenous human platelet TGF-beta 1, activated PKC as reflected by enhanced in situ phosphorylation of MARCKS protein, an endogenous substrate of PKC. U-46619 and TGF-beta 1 stimulated fibronectin (Fn) synthesis in MC, as shown by [35S]methionine incorporation into immunoprecipitable Fn. Pan-specific rabbit anti-TGF-beta antibody blocked the increases in Fn synthesis induced by exogenous TGF-beta and those induced by U-46619 at 24 to 72 hours after addition. Anti-TGF-beta antibody did not block the small increases in FN synthesis observed six hours after addition of U-46619, suggesting that this acute response was not dependent on TGF-beta. Anti-TGF-beta antibody also failed to block activation of PKC by U-46619. U-46619 and 50 nM of the PKC agonist phorbol dibutyrate (PDBu) significantly increased both the active fraction and total (latent plus active) TGF-beta in MC culture media, as assayed with the mink lung epithelial cell bioassay system.(ABSTRACT TRUNCATED AT 250 WORDS)

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http://dx.doi.org/10.1038/ki.1995.310DOI Listing

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