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

TGF-β: the master regulator of fibrosis.

Author information

1
School of Pharmacy and Institute for Kidney Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
2
Department of Nephrology and Monash University Department of Medicine, 246 Clayton Road, Monash Medical Centre, Clayton, Victoria 3168, Australia.
3
Department of Medicine &Therapeutics and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, The New Territories, Hong Kong, China.

Abstract

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.

PMID:
27108839
DOI:
10.1038/nrneph.2016.48
[Indexed for MEDLINE]

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