title: Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice.
abstract: BACKGROUND
  The present study tested the hypothesis that disruption of Smad7 function may accelerate renal fibrosis and inflammation.
  
  
  METHODS
  This was investigated in a unilateral ureteral obstruction (UUO) model induced in wild-type (WT) and Smad7DeltaE1 mice in which functional Smad7 is disrupted by deleting exon I in the Smad7 gene. Renal fibrosis and inflammation after UUO were examined by histology, real-time PCR, western blot analyses and immunohistochemistry.
  
  
  RESULTS
  Seven days after UUO, severe tubulointerstitial fibrosis developed in WT mice as evidenced by a marked increase in alpha-SMA, collagen I and III extracellular matrix. This was associated with a significant upregulation of renal TGF-beta1 and CTGF and activation of Smad2/3. Interestingly, compared to WT UUO mice, Smad7DeltaE1 mice with UUO exhibited a further increase in TGF-beta/Smad2/3-dependent renal fibrosis. Moreover, compared to WT UUO mice, deletion of the Smad7 gene also sustained NF-kappaB activation and thus enhanced further renal inflammation such as macrophage infiltration and upregulation of TNF-alpha, MCP-1, OPN and ICAM-1.
  
  
  CONCLUSIONS
  Smad7 is a critical negative regulator of TGF-beta/Smad2/3 and NF-kappaB signalling and plays a negative regulating role in both renal fibrosis and inflammation after UUO. Results from this study further support the notion that Smad7 may be a therapeutic agent for kidney diseases.
authors.affiliation: Department of Medicine, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China.
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Rainer
authors.initials: R
authors.lastname: Heuchel
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D019892:eIF-2 Kinase