Smad3-dependent and -independent pathways are involved in peritoneal membrane injury

Kidney Int. 2010 Feb;77(4):319-28. doi: 10.1038/ki.2009.436. Epub 2009 Dec 2.


Transition of peritoneal mesothelial cells to a mesenchymal phenotype plays an integral role in the angiogenic and fibrotic changes seen in the peritoneum of patients receiving long-term peritoneal dialysis. While signaling by transforming growth factor (TGF)-beta through Smad proteins likely causes these changes, it is possible that non-Smad pathways may also play a role. Here, we found that Smad3-deficient mice were protected from peritoneal fibrosis and angiogenesis caused by adenovirus-mediated gene transfer of active TGF-beta1 to mesothelial cells; however, mesothelial transition occurred in this setting, suggesting involvement of non-Smad mechanisms. The phosphatidyl inositol 3 kinase (PI3K) target, Akt, was upregulated in both Smad-deficient and wild-type mice after exposure to TGF-beta1. In vivo inhibition of the mammalian target of rapamycin (mTOR) by rapamycin completely abrogated the transition response in Smad3-deficient but not in wild-type mice. Rapamycin blocked nuclear localization of beta-catenin independent of glycogen synthase kinase 3beta activity. Further, in Smad3-deficient mice rapamycin reduced the expression of alpha-smooth muscle actin, which is an epithelial-to-mesenchymal transition-associated gene. Hence, we conclude that TGF-beta1 causes peritoneal injury through Smad-dependent and Smad-independent pathways; the latter involves redundant mechanisms inhibited by rapamycin, suggesting that suppression of both pathways may be necessary to abrogate mesothelial transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Epithelial Cells
  • Mesoderm / cytology
  • Mice
  • Peritoneal Fibrosis / etiology*
  • Peritoneum / pathology*
  • Signal Transduction
  • Smad3 Protein / physiology*


  • Smad3 Protein