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LIF-STAT3 on renal tubular regeneration process examined by Cre/loxP system

Cre/loxP系统检测LIF-STAT3对肾小管再生过程的影响

基本信息

批准号：
18590902
负责人：
MONKAWA Toshiaki
金额：
$ 2.57万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590902/
关键词：
kidney regeneration Cre-loxP LIF Gs15 Snail1 Gsl5 Cre-LoxP STAT3

项目摘要

The purpose of this study is to clarify how the genes involved in LIF-gp 130-STAT3 signal systems act on renal tubular regeneration by Cre/loxP transgenic mice. We succeeded in generating LoxP-LIF mice which expressed LIF in cells expressing Cre. Crossing LoxP-LIF mice with alfa-MHC-Cre mice generated mice in which LIF is highly expressed in myocardiocytes. In the mice, distribution pattern of sympathetic neurons and parasympathetic neurons turned into heart failure pattern. On the other hand, we tried to generated mice in which Cre expresses specifically in renal tubular cells in S3 segment of proximal tubules. However, AQP7-Cre and GGT2-Cre mice did not show S3 segments specific expression of Cre.We analyzed Gsl5-EGFP mice and Gsl5-HB-EGF mice collaborating with Michiko Sekine at Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science. Gsl5 was shown to be localized in the promoter region of core 2 [beta]-1, 6-N-Acetylglucosaminyl transferase, and was shown to be a cis-regulatory element responsible for proximal S3 tubular cell-specific transcription. Utilizing the Gsl5, we generated transgenic mice in which the human heparin-biding EGF-like growth factor (HB-EGF) is specifically expressed in tubular cells in proximal tubule S3 segment. Mice are resistant to diphtheria toxin (DT) because mice HB-EGF does not bind DT. In contrast, human HB-EGF binds DT at high affinity. In Gsl5-HB-EGF, tubular cells in proximal tubule S3 segment were ablated specifically after administration of DT. Using the mice, we clarified the mechanism of acute renal failure and regeneration of tubular cells.The pathological significance of the tubular epithelial-mesenchymal transition (EMT) in kidney diseases is becoming increasingly recognized. We demonstrated that transcriptional factor Snail is involved in renal tubular EMT and that TGF-beta1 regulates Snail at the transcription and protein degradation levels.

本研究的目的是阐明LIF-gp 130-STAT 3信号系统相关基因在Cre/loxP转基因小鼠肾小管再生中的作用。我们成功地产生了LoxP-LIF小鼠，其在表达Cre的细胞中表达LIF。将LoxP-LIF小鼠与α-MHC-Cre小鼠杂交产生LIF在心肌细胞中高度表达的小鼠。在小鼠中，交感神经元和副交感神经元的分布模式转变为心力衰竭模式。另一方面，我们试图产生Cre在近端小管S3段的肾小管细胞中特异性表达的小鼠。然而，AQP 7-Cre和GGT 2-Cre小鼠不显示Cre的S3片段特异性表达。我们与东京都医学科学研究所实验动物科学部门的Sekine博士合作分析了Gsl 5-EGFP小鼠和Gsl 5-HB-EGF小鼠。Gs15显示定位于核心2 [β]-1，6-N-乙酰葡糖胺基转移酶的启动子区，并且显示为负责近端S3小管细胞特异性转录的顺式调节元件。利用Gs15，我们产生了转基因小鼠，其中人肝素结合EGF样生长因子（HB-EGF）特异性表达于近端小管S3段的肾小管细胞中。小鼠对白喉毒素（DT）具有抗性，因为小鼠HB-EGF不结合DT。相反，人HB-EGF以高亲和力结合DT。在Gs15-HB-EGF中，DT特异性地消融近端小管S3段的小管细胞。利用小鼠阐明了急性肾功能衰竭和肾小管细胞再生的机制，肾小管上皮细胞间质转化（EMT）在肾脏疾病中的病理意义日益受到重视。我们证明转录因子Snail参与肾小管EMT，TGF-β 1在转录和蛋白质降解水平调节Snail。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Snail is involved in the renal epithelial-mesenchymal transition

蜗牛参与肾上皮间质转化

DOI：
发表时间：
2007
期刊：
Biochem Biophys Res Commun 362
影响因子：
0
作者：
樋口逸郎;他;Yoshino J
通讯作者：
Yoshino J

Regulation of Snail at the Transcription and Protein Degradation in Renal Epithelial-Mesenchymal Transition

蜗牛对肾上皮-间质转化中转录和蛋白质降解的调节

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
Kimura T;Tomura H;Mogi C;Kuwabara A;Damirin A;Ishizuka T;Sekiguchi A;Ishiwara M;Im DS;Sato K;Murakami M;Okajima F;Jun Yoshino
通讯作者：
Jun Yoshino

腎の再生因子の探索

寻找肾脏再生因子

DOI：
发表时间：
2007
期刊：
医学のあゆみ 220
影响因子：
0
作者：
Tobo M;Tomura H;Mogi C;Wang JQ;Liu JP;Komachi M;Damirin A;Kimura T;Murata N;Kurose H;Sato K;Okajima F.;門川俊明
通讯作者：
門川俊明

Roles of Thymosin-beta 4 and 10 in renal fibrosis

胸腺素-β 4 和 10 在肾纤维化中的作用