The effect of transforming growth factor beta 1 on mesangial cell fibronectin synthesis: increased incorporation into the extracellular matrix and reduced pI but no effect on alternative splicing.
Fibronectin is a multidomain glycoprotein which accumulates in mesangial proliferative glomerulonephritis (MPGN). Recent evidence has implicated transforming growth factor beta (TGF-beta) in the pathogenesis of experimental MPGN. We have, therefore, examined the influence of TGF-beta 1 on mesangial cell fibronectin synthesis. Considering, first, levels of mRNA, TGF-beta 1 increased steady-state fibronectin RNA in cultured mesangial cells by 1.9 times 24 hr after treatment of cycling mesangial cells and by 11.8 times in growth-arrested cells. There was, however, no alteration in fibronectin pre-mRNA splicing in either the EIIIA or IIICS regions. Fibronectin protein concentrations in cell culture supernatants, determined by immunoprecipitation of supernatants from cells labeled with [35S]methionine and by ELISA, were not increased by treatment with TGF-beta 1. Western blots and immunoprecipitation of metabolically labeled cells showed that fibronectin was increased, however, in the deoxycholate-insoluble extracellular matrix ( ECM) of cells stimulated with TGF-beta 1. TGF-beta 1 altered the physicochemical properties of fibronectin in ECM and supernatant such that the isoelectric point of fibronectin, determined from Western blots of 2D SDS-PAGE gels, was reduced so that both became more acidic. These studies demonstrate, therefore, that in addition to increasing its synthesis, TGF-beta 1 increases incorporation of fibronectin into the ECM. Because fibronectin possesses binding sites for other ECM proteins, greater incorporation of fibronectin following TGF-beta 1 treatment may be an important pathogenetic mechanism in mesangial sclerosis. Moreover, the altered charge of fibronectin may increase localization of serum immunoglobulins to the mesangium.[1]References
- The effect of transforming growth factor beta 1 on mesangial cell fibronectin synthesis: increased incorporation into the extracellular matrix and reduced pI but no effect on alternative splicing. McKay, N.G., Khong, T.F., Haites, N.E., Power, D.A. Exp. Mol. Pathol. (1993) [Pubmed]
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