miR-200a Prevents renal fibrogenesis through repression of TGF-β2 expression

Diabetes. 2011 Jan;60(1):280-7. doi: 10.2337/db10-0892. Epub 2010 Oct 15.


Objective: Progressive fibrosis in the diabetic kidney is driven and sustained by a diverse range of profibrotic factors. This study examines the critical role of microRNAs (miRNAs) in the regulation of the key fibrotic mediators, TGF-β1 and TGF-β2.

Research design and methods: Rat proximal-tubular epithelial cells (NRK52E) were treated with TGF-β1 and TGF-β2 for 3 days, and expression of markers of epithelial-to-mesenchymal transition (EMT) and fibrogenesis were assessed by RT-PCR and Western blotting. The expression of miR-141 and miR-200a was also assessed, as was their role as translational repressors of TGF-β signaling. Finally, these pathways were explored in two different mouse models, representing early and advanced diabetic nephropathy.

Results: Both TGF-β1 and TGF-β2 induced EMT and fibrogenesis in NRK52E cells. TGF-β1 and TGF-β2 also downregulated expression of miR-200a. The importance of these changes was demonstrated by the finding that ectopic expression miR-200a downregulated smad-3 activity and the expression of matrix proteins and prevented TGF-β-dependent EMT. miR-200a also downregulated the expression of TGF-β2, via direct interaction with the 3' untranslated region of TGF-β2. The renal expression of miR-141 and miR-200a was also reduced in mouse models representing early and advanced kidney disease.

Conclusions: miR-200a and miR-141 significantly impact on the development and progression of TGF-β-dependent EMT and fibrosis in vitro and in vivo. These miRNAs appear to be intricately involved in fibrogenesis, both as downstream mediators of TGF-β signaling and as components of feedback regulation, and as such represent important new targets for the prevention of progressive kidney disease in the context of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Cell Line
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / physiopathology
  • Down-Regulation
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Extracellular Matrix Proteins / genetics
  • Gene Expression Regulation
  • Gene Silencing
  • Genes, Reporter
  • Humans
  • Kidney Tubules / physiology
  • Luciferases / genetics
  • Mesoderm / cytology
  • Mesoderm / physiology
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / pharmacology*
  • Polymerase Chain Reaction
  • RNA / genetics
  • RNA / isolation & purification
  • Rats
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transfection
  • Transforming Growth Factor beta1 / antagonists & inhibitors
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / immunology
  • Transforming Growth Factor beta2 / antagonists & inhibitors
  • Transforming Growth Factor beta2 / genetics*
  • Transforming Growth Factor beta2 / immunology


  • 3' Untranslated Regions
  • Extracellular Matrix Proteins
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • RNA
  • Luciferases