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NDT Advance Access originally published online on December 18, 2008
Nephrology Dialysis Transplantation 2009 24(5):1443-1454; doi:10.1093/ndt/gfn699
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice

Arthur C. K. Chung1, Xiao R. Huang1, Li Zhou1, Rainer Heuchel2, Kar Neng Lai1 and Hui Y. Lan1

1 Departments of Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China 2 KFC, Center For Clinical Research, Karolinska Hospital Huddinge, Sweden

Correspondence and offprint requests to: Hui Y. Lan, Department of Medicine, The University of Hong Kong, L8-39, Laboratory Block, 21 Sassoon Road, Hong Kong. Tel: +852-28197745; Fax: +852-28162095; E-mail: hylan{at}hku.hk



  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 Smad7{Delta}E1 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-β1 and CTGF and activation of Smad2/3. Interestingly, compared to WT UUO mice, Smad7{Delta}E1 mice with UUO exhibited a further increase in TGF-β/Smad2/3-dependent renal fibrosis. Moreover, compared to WT UUO mice, deletion of the Smad7 gene also sustained NF-{kappa}B activation and thus enhanced further renal inflammation such as macrophage infiltration and upregulation of TNF-{alpha}, MCP-1, OPN and ICAM-1.

Conclusion. Smad7 is a critical negative regulator of TGF-β/Smad2/3 and NF-{kappa}B 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.

Keywords: renal fibrosis; renal inflammation; Smad7; TGF-β signalling; UUO

Received for publication: 14.10.08
Accepted in revised form: 21.11.08


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