Molecular mechanism of renal interstitial fibrosis in urethral obstruction model

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590358
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Wakayama Medical University
• Principal Investigator: MURAGAKI Yasuteru Wakayama Medical University, School of Medicine, Professor, 医学部, 教授 (40190904)
• Project Period (FY): 2005 – 2006
• Keywords: TGF-β / TNF-α / Smad3 / UUO / Snail / EMT

Research Abstract

Renal interstitial fibrosis in mice is caused by unilateral urethral obstruction (UUO). TGF-b is reportedly upregulated in renal tubular epithelial cells in response to injurious stimuli of UUO, causing renal fibrosis associated with epithelial-mesenchymal transition (EMT). We demonstrated using Smad3 knockout mice that Smad3 pathway is central to the pathogenesis of interstitial fibrosis via EMT of renal tubular epithelial cells. In this study, we sought to elucidate the molecular interaction between Smad3 and other molecules in renal tubular epithelial cells when they transform to mesenchymal cells. We generated the transgenic mice that overexpress Smad3 under a CMV promoter, in which lens epithelial cells spontaneously transform to mesenchymal cell about 10 weeks after birth, resulting in cataract. In addition, in a experiment of UUO using TNF-a KO mice, the degree of renal interstitial fibrosis increased in 4 weeks after UUO, whereas no obvious difference was observed between KO and wild-type mice. In the KO kidneys, the expression of Snail, a key molecule for EMT, was elevated, concomitant with the increase of Coll and aSMA. Also, in the experiments using adenoviral gene transfer of Smad7, Bmp7, Id2, and Id3, the corneal wound healing was accelerated and EMT in lens epithelial cells was suppressed. These adenoviral gene transfers are also applied to UUO experiments to examine whether the levels of renal fibrosis can be suppressed.

Research Products

• [Journal Article] Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses inury-induced epithelial-to-mesenchymal transition of lens eptithelium in mice. (2006)
  • Author(s): Saika S et al.
  • Journal Title: Am J Physiol cell Physiol 290・1 Pages: 282-289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Ohnishi Y, Nakajima Y, Muragaki Y, Ooshima A.
  • Journal Title: Am J Physiol Cell Physiol. 290(1) Pages: 282-289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali. (2005)
  • Author(s): Saika S et al.
  • Journal Title: Am J Pathol 166・5 Pages: 1405-1418
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic effects of adenoviral gene transfer of bone morphgenic protein-7 on a corneal alkali injury model in mice. (2005)
  • Author(s): Saika S et al.
  • Journal Title: Lab Invest 85・4 Pages: 474-486
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of Smad7 in mouse eyes accelerates healing of corneal tissue following exposure to alkali. (2005)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Miyamoto T, Ohnishi Y, Sato M, Muragaki Y, Ooshima A, Nakajima Y, Kao WW-Y, Flanders KC, Roberts AB.
  • Journal Title: Am J Pathol 166 Pages: 1405-1418
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali burn model in mice. (2005)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Nakajima Y, Miyamoto T, Ohnishi Y, Kao WW-Y, Muragaki Y, Ooshima A.
  • Journal Title: Lab Invest 85 Pages: 474-486
  • Description: 「研究成果報告書概要(欧文)」より