Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney.
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.
Boutet
Agnès
A
Instituto de Neurociencias de Alicante, CSIC-UMH, Sant Joan d'Alacant, Alicante, Spain.
De Frutos
Cristina A
CA
Maxwell
Patrick H
PH
Mayol
M José
MJ
Romero
J
J
Nieto
M Angela
MA
D000818:Animals; D015820:Cadherins / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000196:embryology* / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D015533:Transcriptional Activation
D015820:Cadherins; C491946:Cdh16 protein, mouse; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta