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Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease

Nature Medicine volume 21, pages 989–997 (2015)Cite this article

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An Erratum to this article was published on 04 February 2016

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Abstract

Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.

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Figure 1: Snail1 reactivation is required for the development of UUO-induced fibrosis.
Figure 2: Renal epithelial cells undergo a partial EMT after UUO.
Figure 3: Snail1 reactivation in renal epithelial cells is required for sustained inflammation in the injured kidney.
Figure 4: Snail1 reactivation is required for the development of folic acid-induced fibrosis.
Figure 5: Snail1-induced fibrosis can be reversed in vivo.
Figure 6: Snail1 inactivation reverts UUO-induced fibrosis in mice.

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Change history

  • 04 September 2015

    In the version of this article initially published, the word 'genetically' was added by the editor to the penultimate sentence of the abstract during proofing of the manuscript. However, the authors used not only a genetic knockout approach but also morpholino-induced inhibition of proper mRNA processing to target Snail1 expression. Thus, the word 'genetically' has been deleted from the sentence to better convey the findings of the report. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank members of A. Nieto's laboratory for their helpful discussions and comments throughout the years. We also thank S. Canals for his advice on statistical analysis, and C. Villena and S. Ingham for the design of Supplementary Figure 10. We are very grateful to P. Igarashi (University of Minnesota Medical School) for providing the Ksp1.3-Cre mice. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2008-01042 and CONSOLIDER-INGENIO 2010 CSD2007-00023 and CDS2007-00017), the Generalitat Valenciana (Prometeo 2008/049 and PROMETEOII/2013/002) and the European Research Council (ERC AdG 322694) to M.A.N. The Instituto de Neurociencias is a Centre of Excellence Severo Ochoa. M.T.G. was a recipient of a contract from the Junta de Ampliación de Estudios program at the Consejo Superior de Investigaciones Científicas European Social Fund.

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Author notes

  1. M Teresa Grande, Cristina A De Frutos, Agnès Boutet & R Grant Rowe

    Present address: Present addresses: Department of Biotechnology, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain (M.T.G.); Brain Development and Plasticity Group, Institut de Biologie de l'École Normale Supérieure, Paris, France (C.A.D.F.); CNRS, Sorbonne Université, Université Pierre et Marie Courie, Roscoff, France (A.B.); and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA (R.G.R.).,

  2. M Teresa Grande and Berta Sánchez-Laorden: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain

    M Teresa Grande, Berta Sánchez-Laorden, Cristina López-Blau, Cristina A De Frutos, Agnès Boutet & M Angela Nieto

  2. University of Salamanca, Campus Miguel de Unamuno, Salamanca, Spain

    Miguel Arévalo & José M López-Novoa

  3. Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain

    Miguel Arévalo & José M López-Novoa

  4. Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    R Grant Rowe & Stephen J Weiss

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Contributions

M.T.G. and B.S.-L. performed the majority of experiments, analyzed the data and contributed to writing the manuscript. C.L.-B. was instrumental in the surgery, and histological and expression studies. C.A.F. and A.B. started the project, R.G.R. and S.J.W. provided the Snai1loxP mice before publication, J.M.L.-N. and M.A. quantified Sirius red staining and J.M.L.-N. helped in the interpretation of data. M.A.N. conceived the project, interpreted the data and wrote the manuscript.

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Correspondence to M Angela Nieto.

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Grande, M., Sánchez-Laorden, B., López-Blau, C. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med 21, 989–997 (2015). https://doi.org/10.1038/nm.3901

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