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

• Published in: Nephrology, dialysis, transplantation Vol. 24; no. 5; pp. 1443 - 1454
• Main Authors: Chung, Arthur C. K., Huang, Xiao R., Zhou, Li, Heuchel, Rainer, Lai, Kar Neng, Lan, Hui Y.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2009; Oxford Publishing Limited (England)
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Disease Models, Animal; eIF-2 Kinase - metabolism; Emergency and intensive care: renal failure. Dialysis management; Fibrosis; Inflammation - metabolism; Inflammation - pathology; Intensive care medicine; Kidney - metabolism; Kidney - pathology; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Knockout; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; NF-kappa B - metabolism; Renal failure; renal fibrosis; renal inflammation; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Smad7; Smad7 Protein - genetics; Smad7 Protein - metabolism; TGF-β signalling; Transforming Growth Factor beta - metabolism; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; UUO; renal fibrosis; TGF-β signalling; renal inflammation; Smad7; UUO; Kidney disease; Urinary system disease; Hemodialysis; Rodentia; Inflammation; Obstruction; Extrarenal dialysis; Vertebrata; Mammalia; Mouse; Animal; Fibrosis; Renal failure
• ISSN: 0931-0509; 1460-2385; 1460-2385
• DOI: 10.1093/ndt/gfn699

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 Smad7ΔE1 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 α-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, Smad7ΔE1 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-κB activation and thus enhanced further renal inflammation such as macrophage infiltration and upregulation of TNF-α, MCP-1, OPN and ICAM-1. Conclusion. Smad7 is a critical negative regulator of TGF-β/Smad2/3 and NF-κB 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.