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.

CONCLUSION:

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: Arthur C K Chung, Xiao R Huang, Li Zhou, Rainer Heuchel, Kar Neng Lai, Hui Y Lan
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 24 Issue 5 Pg. 1443-54 (May 2009) ISSN: 1460-2385 [Electronic] England
• PMID: 19096081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Smad7 Protein
• Smad7 protein, mouse
• Transforming Growth Factor beta
• eIF-2 Kinase

Topics

• Animals
• Disease Models, Animal
• Fibrosis
• Inflammation (metabolism, pathology)
• Kidney (metabolism, pathology)
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Signal Transduction
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Smad7 Protein (genetics, metabolism)
• Transforming Growth Factor beta (metabolism)
• Ureteral Obstruction (metabolism, pathology)
• eIF-2 Kinase (metabolism)