Thromboxane A2 (TXA2) has been implicated in the pathogenesis of progressive glomerulosclerosis and stimulates the synthesis of matrix protein by mesangial cells (MCs). This study examined the role of transforming growth factor β (TGF-β) in the mediation of the action of the stable TXA2/prostaglandin (PG) endoperoxide analog U-46619 to stimulate fibronectin (Fn) synthesis in cultured rat MC. Exogenous TGF-β increased Fn synthesis by MC in a concentration- and time-dependent fashion, as reflected by incorporation of [35S]methionine into immunoprecipitable Fn. Submaximal concentrations of TGF-β (1–2.5 pmol/l) increased Fn synthesis two- to threefold, a response comparable in magnitude to that observed with a maximal stimulatory concentration (1 μmol/l) of U-46619. Anti-TGF-β antibody, but not isotypic IgG, blocked the increases in Fn synthesis induced by both U-46619 and exogenous TGF-β. Endogenous TGF-β bioactivity in MC culture media, assessed by the mink lung epithelial cell system, was significantly increased by 1 μmol/l U-46619 (1.7 ± 0.3 pmol/l) compared with that of control media (0.6 ± 0.1 pmol/l, P < 0.05). Total (active plus latent) TGF-β bioactivity, assayed after heat activation of latent TGF-β, was also significantly higher in media of MCs cultured with U-46619 (45 ± 4 pmol/l) compared with control (24 ± 4 pmol/l). Thus, U-46619 increased endogenous TGF-β bioactivity to a level sufficient to account for the enhancement of Fn synthesis observed with U-46619, as reflected by the Fn synthetic response to exogenous TGF-β. This finding, together with the inhibitory effect of anti-TGF-β antibody on Fn synthesis, implicates TGF-β in expression of this action of U-46619.

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