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Fibrosis

Targeting EMT to reverse renal fibrosis

Nature Reviews Nephrology volume 11, page 565 (2015)Cite this article

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Epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells is a feature of renal fibrosis, but the contribution of EMT to the myofibroblast population and the importance of EMT to the fibrotic process are unclear. Two studies published in Nature Medicine now show that partial EMT is required for the development of renal fibrosis. These studies demonstrate that the partial EMT response does not directly generate interstitial myofibroblasts but rather induces signals that stimulate myofibroblast differentiation and inflammation, suggesting that EMT could be targeted for the treatment of renal fibrosis. “In contrast to the situation in embryonic and cancer cells where the EMT endows cells with invasive properties, renal epithelial cells respond to the activation of EMT inducers by undergoing epithelial dedifferentiation but do not engage in delamination or invasion programmes,” says Angela Nieto. “Thus our results help to reconcile previous apparently conflicting data with regard to the role of EMT in fibrosis.”

As previous research had demonstrated a link between chronic kidney disease and inadequate epithelial cell cycle progression, Kalluri and colleagues used their conditional knockout mice to investigate the potential contribution of EMT to G2/M arrest of tubular epithelial cells. Using flow cytometry and immunohistochemical analyses, they found that deletion of Twist1 and Snai1 in tubular epithelial cells attenuated the cell-cycle arrest induced by UUO. In a mouse proximal tubular epithelial cell line, overexpression of Twist1 and Snai1 or treatment with TGF-β1 induced G2 arrest together with Cdkn1a (p21) expression, whereas silencing of Cdkn1a by RNA interference prevented TGF-β1-induced G2 arrest. “Once the EMT programme is initiated many things happen, including the loss of functioning epithelial cells needed for organ function and the arrest of cell proliferation that is important for cell and tissue regeneration,” explains Kalluri.

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References

  1. Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 10.1038/nm.3901

  2. Lovisa, S. et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat. Med. 10.1038/nm.3902

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  1. Susan J. Allison
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Allison, S. Targeting EMT to reverse renal fibrosis. Nat Rev Nephrol 11, 565 (2015). https://doi.org/10.1038/nrneph.2015.133

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