Epithelial to Mesenchymal Transition induces cell cycle arrest and parenchymal damage in renal fibrosis

By S. Lovisa, Valerie S. LeBleu, B. Tampe, H. Sugimoto, Komal Vadnagara, Julienne L. Carstens, Chia-Chin Wu, Y. Hagos, B. Burckhardt, Tsvetelina Pentcheva-Hoang and 4 more. Nature Medicine, 2015

893 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/d6e25f125b243a4d38ca4ef0d76a7bb3dcc6e1ef

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In Molecular Biology

1. D. Sheppard
2. H. Lan
3. Kevin K. Kim
4. Bi-Cheng Liu
5. H. Chapman
6. L. Lv
7. Jinmiao Chen
8. T. Tang

In Nephrology

1. H. Lan
2. Bi-Cheng Liu
3. L. Lv
4. T. Tang

Citations in the corpus

• Renal tubule injury: a driving force toward chronic kidney disease. (2018, background): “It is also reported that G2/M arrest is associated with EMT and that TGF-b1 is capable of inducing G2/M arrest and EMT in TECs during renal fibrosis via cell-cycle inhibitor p21.(65,209,213)”
• Comparison Between UMAP and t-SNE for Multiplex-Immunofluorescence Derived Single-Cell Data from Tissue Sections (2019, background): “Among the 119 biopsies included and with a median follow-up of 73 months (4-160), 5-year overall survival was 39.”
• TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “In models of kidney fibrosis, epithelial-specific deletion of the genes encoding the EMT transcription factor Snail1 or Twist leads to attenuated fibrosis (Grande et al. 2015; Lovisa et al. 2015).”