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Am J Physiol Renal Physiol (May 20, 2003). doi:10.1152/ajprenal.00082.2003
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Submitted on February 25, 2003
Accepted on May 14, 2003

Smad3 and PKC{delta} mediate TGF-{beta}1-induced collagen I expression in human mesangial cells

Constance E. Runyan1, H. William Schnaper1, and Anne-Christine Poncelet1*

1 Department of Pediatrics W-140, Northwestern University, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: anne-c{at}northwestern.edu.

Transforming growth factor (TGF)-{beta} has been associated with fibrogenesis in clinical studies and animal models. We previously showed that Smad3 promotes COL1A2 gene activation by TGF-{beta}1 in human mesangial cells. In addition to the Smad pathway, it has been suggested that TGF-{beta}1 could also activate more classical growth factor signaling. Here, we report that PKC{delta} plays a role in TGF-{beta}1-stimulated collagen I production. In an in vitro kinase assay, TGF-{beta}1 treatment specifically increased mesangial cell PKC{delta} activity in a time-dependent manner. Translocation to the membrane was detected by immunocytochemistry and immunoblot, suggesting activation of PKC{delta} by TGF-{beta}1. Inhibition of PKC{delta} by rottlerin decreased basal and TGF-{beta}1-stimulated collagen I production, mRNA expression and COL1A2 promoter activity, while blockade of conventional PKCs by Go 6976 had little or no effect. In a Gal4-LUC assay system, inhibition of PKC{delta} abolished TGF-{beta}1-induced transcriptional activity of Gal4-Smad3 and Gal4-Smad4(266-552). Overexpression of Smad3 or Smad3D, in which the three C-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{delta} inhibition, suggesting that rottlerin decreased Smad3 transcriptional activity independently of C-terminal serine phosphorylation. Blockade of PKC{delta} abolished ligand-independent and ligand-dependent stimulation of COL1A2 promoter activity by Smad3. These data indicate that PKC{delta} is activated by TGF-{beta}1 in human mesangial cells. TGF-{beta}1-stimulated PKC{delta} 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.




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