Smad3-dependent and -independent pathways are involved in peritoneal membrane injury.
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.
Patel
Pranali
P
Department of Medicine, McMaster University, Hamilton, Canada.
Sekiguchi
Yoshimi
Y
Oh
Kook-Hwan
KH
Patterson
Sarah E
SE
Kolb
Martin R J
MR
Margetts
Peter J
PJ
D000818:Animals; D002454:Cell Differentiation; D004847:Epithelial Cells; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D056627:Peritoneal Fibrosis / Q000209:etiology*; D010537:Peritoneum / Q000473:pathology*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000502:physiology*
D051900:Smad3 Protein