miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes

Diabetologia. 2013 Mar;56(3):663-74. doi: 10.1007/s00125-012-2804-x. Epub 2013 Jan 5.


Aims/hypothesis: As microRNA-21 (miR-21) plays a pathological role in fibrosis, we hypothesised that it may be a therapeutic target for diabetic nephropathy.

Methods: Abundance of miR-21 was examined in diabetic kidneys from db/db mice. The therapeutic potential of miR-21 in diabetic kidney injury was examined in db/db mice by an ultrasound-microbubble-mediated miR-21 small hairpin RNA transfer. In addition, the role and mechanisms of miR-21 in diabetic renal injury were examined in vitro under diabetic conditions in rat mesangial and tubular epithelial cell lines by overexpressing or downregulating miR-21.

Results: In db/db mice, a mouse model of type 2 diabetes, renal miR-21 at age 20 weeks was increased twofold compared with db/m (+) mice at the same age, and this increase was associated with the development of microalbuminuria and renal fibrosis and inflammation. More importantly, gene transfer of miR-21 knockdown plasmids into the diabetic kidneys of db/db mice at age 10 weeks significantly ameliorated microalbuminuria and renal fibrosis and inflammation at age 20 weeks, revealing a therapeutic potential for diabetic nephropathy by targeting miR-21. Overexpression of miR-21 in kidney cells enhanced, but knockdown of miR-21 suppressed, high-glucose-induced production of fibrotic and inflammatory markers. Targeting Smad7 may be a mechanism by which miR-21 regulates renal injury because knockdown of renal miR-21 restored Smad7 levels and suppressed activation of the TGF-β and NF-κB signalling pathways.

Conclusions/interpretation: Inhibition of miR-21 might be an effective therapy for diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / physiopathology
  • In Situ Hybridization
  • Kidney / metabolism*
  • Kidney / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Rats
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Smad7 Protein
  • Smad7 protein, mouse
  • Transforming Growth Factor beta