Format

Send to

Choose Destination
Nat Med. 2015 Sep;21(9):998-1009. doi: 10.1038/nm.3902. Epub 2015 Aug 3.

Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis.

Author information

1
Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
2
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
3
Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
4
Institute of Systemic Physiology and Pathophysiology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.
5
Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Abstract

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.

PMID:
26236991
PMCID:
PMC4587560
DOI:
10.1038/nm.3902
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center