miR-192 mediates TGF-beta/Smad3-driven renal fibrosis

J Am Soc Nephrol. 2010 Aug;21(8):1317-25. doi: 10.1681/ASN.2010020134. Epub 2010 May 20.

Abstract

TGF-beta/Smad3 promotes renal fibrosis, but the mechanisms that regulate profibrotic genes remain unclear. We hypothesized that miR-192, a microRNA expressed in the kidney may mediate renal fibrosis in a Smad3-dependent manner. Microarray and real-time PCR demonstrated a tight association between upregulation of miR-192 in the fibrotic kidney and activation of TGF-beta/Smad signaling. Deletion of Smad7 promoted miR-192 expression and enhanced Smad signaling and fibrosis in obstructive kidney disease. In contrast, overexpression of Smad7 to block TGF-beta/Smad signaling inhibited miR-192 expression and renal fibrosis in the rat 5/6 nephrectomy model; in vitro, overexpression of Smad7 in tubular epithelial cells abolished TGF-beta1-induced miR-192 expression. Furthermore, Smad3 but not Smad2 mediated TGF-beta1-induced miR-192 expression by binding to the miR-192 promoter. Last, overexpression of a miR-192 mimic promoted and addition of a miR-192 inhibitor blocked TGF-beta1-induced collagen matrix expression. Taken together, miR-192 may be a critical downstream mediator of TGF-beta/Smad3 signaling in the development of renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibrosis / etiology
  • Kidney / pathology*
  • Mice
  • MicroRNAs / physiology*
  • Rats
  • Smad3 Protein / physiology*
  • Transforming Growth Factor beta / physiology*

Substances

  • MicroRNAs
  • Mirn192 microRNA, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta