Clinical Science (2013) 124, 243–254 (Printed in Great Britain) doi: 10.1042/CS20120252 Role of the TGF-β /BMP-7/Smad pathways in renal diseases Xiao-Ming MENG ∗ †‡, Arthur C. K. CHUNG ∗ †‡ and Hui Y. LAN ∗ †‡ ∗ CUHK Shenzhen Research Institute, Shenzhen, Guangdong Province, China †Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, The New Territories, Hong Kong, China ‡Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The New Territories, Hong Kong, China Abstract 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-β 1 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-β 1 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. Key words: bone morphogenetic protein-7 (BMP-7), inflammation, renal fibrosis, Smad, transforming growth factor-β (TGF-β) INTRODUCTION The TGF-β (transforming growth factor-β ) superfamily con- tains highly pleiotropic molecules, such as TGF-β , BMPs (bone morphogenic proteins), activins, inhibins, GDFs (growth differ- entiation factors) and GDNFs (glial-derived neurotrophic factors) [1]. It is now well accepted that TGF-β acts as an essential me- diator in kidney diseases given its multiple functions in renal fibrosis, inflammation, cell growth, apoptosis and differentiation, whereas BMP-7 exhibits its antifibrotic and anti-inflammatory properties [2–5]. Abbreviations used: 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. Correspondence: Dr Hui Y. Lan (email hylan@cuhk.edu.hk). TGF-β /BMP signalling is mediated by heterodimeric re- ceptors with serine/threonine receptor kinases and cytoplas- mic proteins called Smads [1]. TGF-β binds its Tβ RII (type II TGF-β receptor) to activate Tβ RI (type I TGF-β receptor) to convey intracellular signals through phosphorylation of R- Smads (receptor-regulated Smads), including Smad2 and Smad3. On the other hand, BMP-7 binds BMPRs (BMP receptors) to activate R-Smad1/5/8. Phosphorylated R-Smads will form heteromeric complexes with a common partner, Smad4 (co- Smad). The complex then translocates into the nucleus to induce the transcription of their target genes. However, the www.clinsci.org 243