期刊
NATURE MEDICINE
卷 21, 期 9, 页码 998-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.3902
关键词
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资金
- University of Texas M.D. Anderson Cancer Center (UT MDACC)
- Cancer Prevention and Research Institute of Texas
- University of Texas System Science and Technology Acquisition and Retention (STARS) awards
- US National Institutes of Health (NIH) [CA-155370, CA-151925, DK-081576, DK-55001]
- Metastasis Research Center at the M.D. Anderson Cancer Center [P30CA016672]
- NIH [P30CA016672]
- Khalifa Bin Zayed Al Nahya Foundation
- NIH through MDACC Support grant [CA-016672]
- Deutsche Forschungsgemeinschaft [INST1525/16-1 FUGG]
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-beta 1-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.
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