A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells

Kidney Int. 2011 Aug;80(4):358-68. doi: 10.1038/ki.2011.43. Epub 2011 Mar 9.


Enhanced transforming growth factor-β1 (TGF-β1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-β1 promoter is positively controlled by the E-box regulators, upstream stimulatory factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-β1 is autoregulated by itself. As changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-β1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-β1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-β1 promoter was upregulated by TGF-β1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-β1 expression. TGF-β1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-β1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1, and TGF-β1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-β1 signaling, accelerating chronic fibrotic diseases such as diabetic nephropathy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Binding Sites
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Collagen Type IV / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Fibrosis
  • Homeodomain Proteins / metabolism
  • Homeostasis
  • Kruppel-Like Transcription Factors / metabolism
  • Mesangial Cells / metabolism*
  • Mice
  • MicroRNAs / metabolism*
  • Mutation
  • Oligonucleotides / metabolism
  • Promoter Regions, Genetic
  • Time Factors
  • Transfection
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*
  • Up-Regulation
  • Upstream Stimulatory Factors / metabolism
  • Zinc Finger E-box-Binding Homeobox 1


  • 3' Untranslated Regions
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Collagen Type I
  • Collagen Type IV
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • MicroRNAs
  • Mirn192 microRNA, mouse
  • Mirn200 microRNA, mouse
  • Oligonucleotides
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Upstream Stimulatory Factors
  • Usf1 protein, mouse
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • Tcfe3 protein, mouse