Molecular mechanism of renal interstitial fibrosis in urethral obstruction model

尿道梗阻模型肾间质纤维化的分子机制

• 批准号: 17590358
• 负责人: MURAGAKI Yasuteru
• 金额: $ 2.24万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590358/
• 关键词: TGF-β; TNF-α; Smad3; UUO; Snail; EMT

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.

单侧尿道梗阻（UUO）可引起小鼠肾间质纤维化。据报道，TGF-β在肾小管上皮细胞中响应于UUO的有害刺激而上调，引起与上皮-间质转化（EMT）相关的肾纤维化。我们使用Smad 3基因敲除小鼠证明，Smad 3途径是通过肾小管上皮细胞的EMT的间质纤维化的发病机制的中心。在这项研究中，我们试图阐明Smad 3和其他分子在肾小管上皮细胞转化为间充质细胞时的分子相互作用。我们建立了在CMV启动子下过表达Smad 3的转基因小鼠，其中出生后约10周，透镜上皮细胞自发转化为间充质细胞，导致白内障。此外，在使用TNF-α KO小鼠的UUO实验中，在UUO后4周肾间质纤维化程度增加，而KO和野生型小鼠之间没有观察到明显差异。在KO肾脏中，EMT的关键分子Snail的表达升高，伴随着科尔和aSMA的增加。另外，在使用Smad 7、Bmp 7、Id 2和Id 3的腺病毒基因转移的实验中，角膜创伤愈合被加速并且透镜上皮细胞中的EMT被抑制。这些腺病毒基因转移也被应用于UUO实验，以检查肾纤维化的水平是否可以被抑制。

项目成果

Expression of Smad7 in mouse eyes accelerates healing of corneal tissue following exposure to alkali.

小鼠眼睛中 Smad7 的表达可加速接触碱后角膜组织的愈合。

• 发表时间: 2005
• 期刊: Am J Pathol 166
• 作者: Saika S;Ikeda K;Yamanaka O;Miyamoto T;Ohnishi Y;Sato M;Muragaki Y;Ooshim A;Nakajima Y;Kao WW-Y;Flanders KC;Roberts AB.
• 通讯作者: Roberts AB.

Direct maxacalcitol injection into hyperplastic parathyroids improves skeletal changes in secondary hyperparathyroidism

直接注射马沙骨化醇至增生性甲状旁腺可改善继发性甲状旁腺功能亢进症的骨骼变化

• 发表时间: 2006
• 期刊: Kidney Int.2006 70(3)
• 作者: Shiizaki K;Hatamura I;Negi S;Sakaguchi T;Saji F;Kunimoto K;Okamoto M;Imazeki I;Muragaki Y;Akizawa T
• 通讯作者: Akizawa T

Combination gene therapy of HGF and truncated type II TGF-β receptor for rat liver cirrhosis after partial hepatectomy

• DOI: 10.1016/j.surg.2005.10.003
• 发表时间: 2006-04-01
• 期刊: SURGERY
• 影响因子: 3.8
• 作者: Ozawa, S;Uchiyama, K;Yamaue, H
• 通讯作者: Yamaue, H

adenoviral gene transfer of BMP-7, ld2, or ld3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice.

BMP-7、ld2 或 ld3 的腺病毒基因转移可抑制小鼠损伤诱导的晶状体上皮细胞上皮间质转化。

• 发表时间: 2006
• 期刊: Am J Physiol Cell Physiol. 290・1
• 作者: Saika S;Ikeda K;Yamanaka O;Flanders KC;Ohnishi Y;Nakajima Y;Muragaki Y;Ooshima A.;Shiizaki K et al.;Saika S et al.
• 通讯作者: Saika S et al.

Therapeutic effects of adenoviral gene transfer of bone morphgenic protein-7 on a corneal alkali injury model in mice.

腺病毒基因转移骨形态发生蛋白7对小鼠角膜碱损伤模型的治疗作用。

• 发表时间: 2005
• 期刊: Lab Invest 85・4
• 作者: Makoto Endo;Tadashi Hasegawa;et al.;A.Makiyama;Saika S et al.
• 通讯作者: Saika S et al.