title: Role of the TGF-β/BMP-7/Smad pathways in renal diseases.
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-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.
authors.affiliation: CUHK Shenzhen Research Institute, Shenzhen, Guangdong Province, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D012076:Renal Agents / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D012076:Renal Agents; D051785:Smad Proteins; D016212:Transforming Growth Factor beta