TY - JOUR
T1 - Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis
AU - Lovisa, Sara
AU - LeBleu, Valerie S.
AU - Tampe, Björn
AU - Sugimoto, Hikaru
AU - Vadnagara, Komal
AU - Carstens, Julienne L.
AU - Wu, Chia Chin
AU - Hagos, Yohannes
AU - Burckhardt, Birgitta C.
AU - Pentcheva-Hoang, Tsvetelina
AU - Nischal, Hersharan
AU - Allison, James P.
AU - Zeisberg, Michael
AU - Kalluri, Raghu
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/9/8
Y1 - 2015/9/8
N2 - Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.
AB - Kidney fibrosis is marked by an epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs). Here we find that, during renal fibrosis, TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of the EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several solute and solvent transporters in TECs. We also found that transgenic expression of either Twist1 (encoding twist family bHLH transcription factor 1, known as Twist) or Snai1 (encoding snail family zinc finger 1, known as Snail) expression is sufficient to promote prolonged TGF-β1-induced G2 arrest of TECs, limiting the cells' potential for repair and regeneration. In mouse models of experimentally induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while also restoring cell proliferation, dedifferentiation-associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of the EMT program in TECs during chronic renal injury represents a potential anti-fibrosis therapy.
UR - http://www.scopus.com/inward/record.url?scp=84941007847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84941007847&partnerID=8YFLogxK
U2 - 10.1038/nm.3902
DO - 10.1038/nm.3902
M3 - Article
C2 - 26236991
AN - SCOPUS:84941007847
SN - 1078-8956
VL - 21
SP - 998
EP - 1009
JO - Nature medicine
JF - Nature medicine
IS - 9
ER -