TGF-β acts on multiple cell types to drive fibrosis in progressive kidney disease
TGF-β signals through both canonical and non-canonical pathways; TGF-β canonical signalling via Smads has a central role in the development of renal fibrosis
The profibrotic actions of TGF-β are positively and negatively regulated by interactions with other signalling pathways and by noncoding RNA and epigenetic mechanisms
Direct targeting of TGF-β is unlikely to be therapeutically feasible due to the involvement of TGF-β in other systems, including the immune system
Greater understanding of the fibrotic pathways regulated by TGF-β has identified alternative therapeutic targets; re-establishing the balance between profibrotic Smad3 activation and antifibrotic Smad7 action is once such approach
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.
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We apologize to all colleagues whose important findings could not be cited owing to space limitations. The authors' work described in this Review was supported by a Major State Basic Research Development Program of China (973 program, No. 2012CB517705), the Research Grants Council of Hong Kong (GRF 468711, CUHK3/CRF/12R), the Focused Investment Scheme A from Chinese University of Hong Kong, and the National Natural Science Foundation of China (No. 81300580, No. 81570623). D.J.N.-P. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.
D.J.N.-P. has worked as a consultant and received research funding from Celgene and Gilead Sciences, and is a co-inventor on a patent for a Smad3 inhibitor (Australian Application number 2015900903). X.-M.M. and H.Y.L. declare no competing interests.
- CpG islands
Short DNA sequences that contain an atypically high frequency of cytosine–phosphate–guanine (CpG) sites; such sites generally lack DNA (cysteine) methylation and associate with the majority of annotated gene promoters.
- CpG shores
Regions of comparatively low CpG density that flank traditional CpG islands.
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Meng, Xm., Nikolic-Paterson, D. & Lan, H. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol 12, 325–338 (2016). https://doi.org/10.1038/nrneph.2016.48
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