TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-β/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-β/Smad3 signalling and protects the kidney from TGF-β-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-β/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-β and BMP-7 in CKDs implies that targeting the TGF-β/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.
- bone morphogenetic protein-7 (BMP-7)
- renal fibrosis
- transforming growth factor-β (TGF-β)
Abbreviations: BMP, bone morphogenic protein; BMPR, BMP receptor; CKD, chronic kidney disease; Col1A2, collagen type 1α2 gene; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EndoMT, endothelial–mesenchymal transition; ERK, extracellular-signal-regulated kinase; FSP-1, fibroblast-specific protein-1; IL, interleukin; IκBα, inhibitory κBα; KO, knockout; MAPK, mitogen-activated protein kinase; MC, mesangial cell; MCP-1, monocyte chemoattractant protein-1; miR, microRNA; MMP, matrix metalloproteinase; NF-κB, nuclear factor κB; α-SMA, α-smooth muscle actin; TEC, tubular epithelial cell; TGF, transforming growth factor; LTBP, latent TGF-β-binding protein; TIMP, tissue inhibitor of metalloproteinase; TNF-α, tumour necrosis factor-α; TβRI etc., type I TGF-β receptor etc.; USAG-1, uterine sensitization associated gene-1; VEGF, vascular endothelial growth factor; ZEB, zinc finger E-box-binding homeobox
- © The Authors Journal compilation © 2013 Biochemical Society