CTGF expression in mesangial cells: Involvement of SMADs, MAP kinase, and PKC.

The induction of excess matrix in renal fibrosis seems to be mediated, at least in part, by the transforming growth factor-β (TGF-β)-mediated induction of connective tissue growth factor (CTGF) in mesangial cells.

By examining CTGF protein and mRNA expression and promoter activity in the presence or absence of TGF-β or inhibitors, the signaling pathways controlling basal and TGF-β–induced CTGF expression in mesangial cells were investigated.

TGF-β enhances CTGF mRNA and protein expression in mesangial cells. Mutation of a consensus SMAD binding element in the CTGF promoter completely abolished TGF-β–induced CTGF expression and reduced basal CTGF expression. The previously identified basal control element-1 (BCE-1) site, but not Sp1 contributes to basal CTGF promoter activity. Ras/MEK/ERK, protein kinase C (PKC) and tyrosine kinase activity also contribute to basal and TGF-β–induced CTGF promoter activity in cultured mesangial cells.

The TGF-β–induction of CTGF in mesangial cells requires SMADs and PKC/ras/MEK/ERK pathways. SMADs are involved in basal CTGF expression, which presumably reflects the fact that mesangial cells express TGF-β endogenously. TGF-β also induces CTGF through ras/MEK/ERK. Inhibiting ras/MEK/ERK seems not to reduce phosphorylation (that is, activation) of SMADs, suggesting that SMADs, although necessary, are insufficient for the TGF-β–stimulation of the CTGF promoter through ras/MEK/ERK. Thus, maximal TGF-β induction of CTGF requires synergy between SMAD and ras/MEK/ERK signaling.