Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction.

Abstract

BACKGROUND:

Transforming growth factor-beta (TGF-beta) has been implicated in the development of renal fibrosis induced by unilateral ureteral obstruction (UUO). However, there is little information on signaling pathways mediating TGF-beta activity involved in molecular and cellular events leading to renal fibrosis induced by UUO. In this study, we sought to determine whether Smad3, a major signaling component of TGF-beta, mediated renal fibrosis induced by UUO.

METHODS:

Renal fibrosis, inflammation, and apoptosis induced by UUO were macroscopically and histologically compared between wild-type mice and Smad3 null mice.

RESULTS:

Gross appearance of the kidney after UUO showed relatively intact kidney in Smad3 null mice [Smad3(-/-) mice] when compared with that of wild-type mice [Smad3(+/+) mice]. Renal interstitial fibrosis based on the interstitial area stained with Aniline-blue or Sirius red solution was significantly attenuated in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Deposition of type I and type III collagens were also significantly reduced in the obstructed kidney of Smad3(-/-) mice. In addition, the numbers of myofibroblasts, macrophages, and CD4/CD8 T cells infiltrated into the kidney after UUO were significantly attenuated in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Furthermore, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining after UUO showed significantly reduced number of tubular apoptotic cells in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice. Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area.

CONCLUSION:

Smad3 deficiency attenuated renal fibrosis, inflammation, and apoptosis after UUO, suggesting that Smad3 was a key molecule mediating TGF-beta activity leading to real fibrosis after UUO.

• Authors: Kumi Inazaki, Yutaka Kanamaru, Yuko Kojima, Noriyoshi Sueyoshi, Ko Okumura, Kazunari Kaneko, Yuichiro Yamashiro, Hideoki Ogawa, Atsuhito Nakao
• Journal: Kidney international (Kidney Int) Vol. 66 Issue 2 Pg. 597-604 (Aug 2004) ISSN: 0085-2538 [Print] United States
• PMID: 15253712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Trans-Activators

Topics

• Animals
• Apoptosis
• DNA-Binding Proteins (genetics, metabolism)
• Fibrosis
• Kidney (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Nephritis (immunology, pathology, physiopathology)
• Phenotype
• Phosphorylation
• Smad2 Protein
• Smad3 Protein
• Trans-Activators (genetics, metabolism)
• Ureteral Obstruction (immunology, pathology, physiopathology)