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

Abstract

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.

TGF-β1 Stimulates Mouse Macrophages to Express APRIL through Smad and p38MAPK/CREB Pathways

“…In the TAK1 pathway, TGF-β1 activates TAK1-MKK6-p38MAPK (Hanafusa et al, 1999) and CREB, p38 MAPK downstream molecules (Chen and Xie, 2010;Johannessen et al, 2004). Between the two pathways, we do not distinguish at the moment which pathway is more relevant to TGFβ1-induced APRIL expression as often demonstrated by others (Hanafusa et al, 1999;Kamaraju and Roberts, 2005;Patel et al, 2010). We have previously shown that TGF-β1 induces the expression of BAFF, another TNF family member, mainly through Smad3/4 signaling (Kim et al, 2008).…”

Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage

“…In the peritoneal tissue of PD fluidinstilled mice there was accumulation of FSP-1 ϩ fibroblasts, and different numbers of these fibroblasts co-expressed cytokeratin ( Figure In previous studies, it was shown that TGF-␤1 overexpression reproduced the structural and functional alterations of the peritoneum observed in PD patients and that MMT appeared during the early stages (days 4 to 7) of peritoneal damage. [33][34][35] To characterize the different subpopulations of activated fibroblasts in response to TGF-␤1 overexpression, adenovirus-mediated gene transfer experiments were carried out. Mice were infected with control adenovirus or adenovirus encoding active TGF-␤1 by intraperitoneal injection.…”

“…30 -32 The relevance of TGF-␤1 in peritoneal damage is further suggested in experimental animal models in which the TGF-␤1 gene is transduced into the peritoneal cavity with adenovirus vectors, recapitulating the structural and functional alterations observed in PD patients. [33][34][35] Overexpression of molecules counteracting TGF-␤1-triggered Smad signaling, including Smad-7 and bone morphogenic protein-7, prevents and reverses PD fluidinduced peritoneal worsening. 36 -40 Furthermore, inhibition of TGF-␤1-induced Smad-independent pathways ameliorates the peritoneal membrane alterations in different experimental models.…”

Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury

“…EMT is a process by which epithelial cells lose their polarity and gain migratory capacity in embryogenesis, tissue repair, organ fibrosis, and tumor invasion and metastasis (4). TGF-β signaling, implicated in EMT, suppresses expression of E-cadherin (CDH1), Zo1 (TJP1), and cytokeratin (KRT) while inducing vimentin (VIM) and α-smooth muscle actin (ACTA2) in peritoneal MCs (3,5).…”