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Smad3 and PKC mediate TGF-₁-induced collagen I expression in human mesangial cells

Department of Pediatrics, Northwestern University, Chicago, Illinois 60611

Submitted 25 February 2003 ; accepted in final form 14 May 2003

Transforming growth factor (TGF)- has been associated with fibrogenesis in clinical studies and animal models. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-₁ in human mesangial cells. In addition to the Smad pathway, it has been suggested that TGF-₁ could also activate more classical growth factor signaling. Here, we report that protein kinase C (PKC) plays a role in TGF-₁-stimulated collagen I production. In an in vitro kinase assay, TGF-₁ treatment specifically increased mesangial cell PKC activity in a time-dependent manner. Translocation to the membrane was detected by immunocytochemistry and immunoblot, suggesting activation of PKC by TGF-₁. Inhibition of PKC by rottlerin decreased basal and TGF-₁-stimulated collagen I production, mRNA expression, and COL1A2 promoter activity, whereas blockade of conventional PKCs by Gö 6976 had little or no effect. In a Gal4-LUC assay system, inhibition of PKC abolished TGF-₁-induced transcriptional activity of Gal4-Smad3 and Gal4-Smad4(266-552). Overexpression of Smad3 or Smad3D, in which the three COOH-terminal serine phosphoacceptor residues have been mutated, increased activity of the SBE-LUC construct, containing four DNA binding sites for Smad3 and Smad4. This induction was blocked by PKC inhibition, suggesting that rottlerin decreased Smad3 transcriptional activity independently of COOH-terminal serine phosphorylation. Blockade of PKC abolished ligand-independent and ligand-dependent stimulation of COL1A2 promoter activity by Smad3. These data indicate that PKC is activated by TGF-₁ in human mesangial cells. TGF-₁-stimulated PKC activity positively regulates Smad transcriptional activity and is required for COL1A2 gene transcription. Thus cross talk among multiple signaling pathways likely contributes to the pathogenesis of glomerular matrix accumulation.

transforming growth factor- signal transduction; cross talk; gene regulation; extracellular matrix accumulation; glomerulosclerosis

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