Snail Activation Disrupts Tissue Homeostasis and Induces Fibrosis in the Adult Kidney

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Nov 10

PMID 17093497

Citations 158

Authors

Agnes Boutet

Cristina A de Frutos

Patrick H Maxwell

M Jose Mayol

J Romero

M Angela Nieto

Affiliations

Soon will be listed here.

Abstract

During embryonic development, the kidney epithelium originates from cells that undergo a mesenchymal to epithelial transition (MET). The reverse process, epithelium to mesenchyme transition (EMT), has been implicated in epithelial tumor progression and in the fibrosis that leads to end-stage kidney failure. Snail transcription factors induce both natural and pathological EMT, but their implication in renal development and disease is still unclear. We show that Snail genes are downregulated during the MET that occurs during renal development and that this is correlated with Cadherin-16 expression. Snail suppresses Cadherin-16 via the direct repression of the kidney differentiation factor HNF-1beta, a novel route by which Snail disrupts epithelial homeostasis. Indeed, Snail activation is sufficient to induce EMT and kidney fibrosis in adult transgenic mice. Significantly, Snail is also activated in patients with renal fibrosis. Thus, Snail expression is suppressed during renal development and it must remain silent in the mature kidney where its aberrant activation leads to fibrosis.

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References

Thomson R, Igarashi P, Biemesderfer D, Kim R, Soleimani M, Aronson P . Isolation and cDNA cloning of Ksp-cadherin, a novel kidney-specific member of the cadherin multigene family. J Biol Chem. 1995; 270(29):17594-601. DOI: 10.1074/jbc.270.29.17594. View

Fraga M, Herranz M, Espada J, Ballestar E, Paz M, Ropero S . A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 2004; 64(16):5527-34. DOI: 10.1158/0008-5472.CAN-03-4061. View

Feil R, Brocard J, Mascrez B, Lemeur M, Metzger D, Chambon P . Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci U S A. 1996; 93(20):10887-90. PMC: 38252. DOI: 10.1073/pnas.93.20.10887. View

Sefton M, Sanchez S, Nieto M . Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development. 1998; 125(16):3111-21. DOI: 10.1242/dev.125.16.3111. View

Wertz K, Herrmann B . Kidney-specific cadherin (cdh16) is expressed in embryonic kidney, lung, and sex ducts. Mech Dev. 1999; 84(1-2):185-8. DOI: 10.1016/s0925-4773(99)00074-x. View

Whyte D, Li C, Thomson R, Nix S, Zanjani R, Karp S . Ksp-cadherin gene promoter. I. Characterization and renal epithelial cell-specific activity. Am J Physiol. 1999; 277(4):F587-98. DOI: 10.1152/ajprenal.1999.277.4.F587. View

Burzynski S . Aging: gene silencing or gene activation?. Med Hypotheses. 2004; 64(1):201-8. DOI: 10.1016/j.mehy.2004.06.010. View

Postlethwaite A, Shigemitsu H, Kanangat S . Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol. 2004; 16(6):733-8. DOI: 10.1097/01.bor.0000139310.77347.9c. View

Ryu J, Song S, Han J, Chu Y, Lee M, Kim J . Establishment of penile fibrosis model in a rat using mouse NIH 3T3 fibroblasts expressing transforming growth factor beta1. Biol Reprod. 2004; 72(4):916-21. DOI: 10.1095/biolreprod.104.035089. View

10.

Lin J, Patel S, Cheng X, Cho E, Levitan I, Ullenbruch M . Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease. Nat Med. 2005; 11(4):387-93. DOI: 10.1038/nm1217. View

11.

Vongwiwatana A, Tasanarong A, Rayner D, Melk A, Halloran P . Epithelial to mesenchymal transition during late deterioration of human kidney transplants: the role of tubular cells in fibrogenesis. Am J Transplant. 2005; 5(6):1367-74. DOI: 10.1111/j.1600-6143.2005.00843.x. View

12.

Barrallo-Gimeno A, Nieto M . The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005; 132(14):3151-61. DOI: 10.1242/dev.01907. View

13.

Slattery C, Campbell E, McMorrow T, Ryan M . Cyclosporine A-induced renal fibrosis: a role for epithelial-mesenchymal transition. Am J Pathol. 2005; 167(2):395-407. PMC: 1603578. DOI: 10.1016/S0002-9440(10)62984-7. View

14.

Huber M, Kraut N, Beug H . Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005; 17(5):548-58. DOI: 10.1016/j.ceb.2005.08.001. View

15.

McMorrow T, Gaffney M, Slattery C, Campbell E, Ryan M . Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant. 2005; 20(10):2215-25. DOI: 10.1093/ndt/gfh967. View

16.

Melk A, Mansfield E, Hsieh S, Hernandez-Boussard T, Grimm P, Rayner D . Transcriptional analysis of the molecular basis of human kidney aging using cDNA microarray profiling. Kidney Int. 2005; 68(6):2667-79. DOI: 10.1111/j.1523-1755.2005.00738.x. View

17.

Edghill E, Bingham C, Ellard S, Hattersley A . Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet. 2005; 43(1):84-90. PMC: 2564507. DOI: 10.1136/jmg.2005.032854. View

18.

Liu Y . Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006; 69(2):213-7. DOI: 10.1038/sj.ki.5000054. View

19.

Alexakis C, Maxwell P, Bou-Gharios G . Organ-specific collagen expression: implications for renal disease. Nephron Exp Nephrol. 2005; 102(3-4):e71-5. DOI: 10.1159/000089684. View

20.

Thiery J, Sleeman J . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7(2):131-42. DOI: 10.1038/nrm1835. View