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.
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: Xiao Ming Meng; Xiao Ru Huang; Arthur C K Chung; Wei Qin; Xinli Shao; Peter Igarashi; Wenjun Ju; Erwin P Bottinger; Hui Yao Lan Journal: J Am Soc Nephrol Date: 2010-07-01 Impact factor: 10.121
Authors: Jennifer Y Lai; Jinghui Luo; Christopher O'Connor; Xiaohong Jing; Viji Nair; Wenjun Ju; Ann Randolph; Iddo Z Ben-Dov; Regina N Matar; Daniel Briskin; Jiri Zavadil; Robert G Nelson; Thomas Tuschl; Frank C Brosius; Matthias Kretzler; Markus Bitzer Journal: J Am Soc Nephrol Date: 2014-08-21 Impact factor: 10.121