Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice.
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.
Chung
Arthur C K
AC
Department of Medicine, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China.
Huang
Xiao R
XR
Zhou
Li
L
Heuchel
Rainer
R
Lai
Kar Neng
KN
Lan
Hui Y
HY
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
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