The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression.
Most chronic kidney injuries inevitably progress to irreversible renal fibrosis. Tubular epithelial-to-mesenchymal transition (EMT) is recognized to play pivotal roles in the process of renal fibrosis. However, a comprehensive understanding of the pathogenesis of renal scar formation and progression remains an urgent task for renal researchers. The endogenously produced microRNAs (miRNAs), proved to play important roles in gene regulation, probably regulate most genes involved in EMT. In this study, we applied microarray analysis to investigate the expression profiles of miRNA in murine interstitial fibrotic kidneys induced by unilateral ureteral obstruction (UUO). It was found that miR-200a and miR-141, two members of the miR-200 family, were downregulated at the early phase of UUO. In TGF-β1-induced tubular EMT in vitro, it was also found that the members of the miR-200 family were downregulated in a Smad signaling-dependent manner. It was demonstrated that the miR-200 family was responsible for protecting tubular epithelial cells from mesenchymal transition by target suppression of zinc finger E-box-binding homeobox (ZEB) 1 and ZEB2, which are E-cadherin transcriptional repressors. The results suggest that downregulation of the miR-200 family initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which might provide important targets for novel therapeutic strategies.
Jiangsu Diabetes Center; Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical Univ., Nanjing, Jiangsu Province, China.
Mingxia
M
Xiong
Lei
L
Jiang
Yang
Y
Zhou
Wenjing
W
Qiu
Li
L
Fang
Rouyun
R
Tan
Ping
P
Wen
Junwei
J
Yang
D000818:Animals; D015820:Cadherins / Q000235:genetics; D054337:Cell Dedifferentiation / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005355:Fibrosis; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019459:Urothelium / Q000473:pathology / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; C555600:MIRN200 microRNA, rat; D035683:MicroRNAs; C570644:Mirn141 microRNA, rat; D051785:Smad Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C000630720:ZEB1 protein, rat; D000071799:Zinc Finger E-box-Binding Homeobox 1