PMID- 19956083
OWN - NLM
STAT- MEDLINE
DCOM- 20100604
LR  - 20100201
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Linking)
VI  - 77
IP  - 4
DP  - 2010 Feb
TI  - Smad3-dependent and -independent pathways are involved in peritoneal membrane 
      injury.
PG  - 319-28
LID - 10.1038/ki.2009.436 [doi]
AB  - 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.
FAU - Patel, Pranali
AU  - Patel P
AD  - Department of Medicine, McMaster University, Hamilton, Canada.
FAU - Sekiguchi, Yoshimi
AU  - Sekiguchi Y
FAU - Oh, Kook-Hwan
AU  - Oh KH
FAU - Patterson, Sarah E
AU  - Patterson SE
FAU - Kolb, Martin R J
AU  - Kolb MR
FAU - Margetts, Peter J
AU  - Margetts PJ
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091202
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Smad3 Protein)
SB  - IM
MH  - Animals
MH  - Cell Differentiation
MH  - Epithelial Cells
MH  - Mesoderm/cytology
MH  - Mice
MH  - Peritoneal Fibrosis/*etiology
MH  - Peritoneum/*pathology
MH  - Signal Transduction
MH  - Smad3 Protein/*physiology
EDAT- 2009/12/04 06:00
MHDA- 2010/06/05 06:00
CRDT- 2009/12/04 06:00
PHST- 2009/12/04 06:00 [entrez]
PHST- 2009/12/04 06:00 [pubmed]
PHST- 2010/06/05 06:00 [medline]
AID - S0085-2538(15)54246-4 [pii]
AID - 10.1038/ki.2009.436 [doi]
PST - ppublish
SO  - Kidney Int. 2010 Feb;77(4):319-28. doi: 10.1038/ki.2009.436. Epub 2009 Dec 2.