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 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-beta 1 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-beta/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-beta/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.