TGF-β: the master regulator of fibrosis

Nat Rev Nephrol. 2016 Jun;12(6):325-38. doi: 10.1038/nrneph.2016.48. Epub 2016 Apr 25.


Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibrosis / etiology
  • Histones
  • Humans
  • Kidney / pathology*
  • MicroRNAs / physiology
  • Renal Insufficiency, Chronic / etiology
  • Signal Transduction / physiology
  • Smad Proteins / genetics
  • Smad Proteins / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*


  • Histones
  • MicroRNAs
  • Smad Proteins
  • Transforming Growth Factor beta