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Fundamental Analysis of Regulation of Smadl-related Genes in Diabetic Nephropathy

Smadl相关基因在糖尿病肾病中调控的基础分析

基本信息

批准号：
17590853
负责人：
ABE Hideharu
金额：
$ 2.18万
依托单位：
Research Institute for Production Development
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-17590853/
关键词：
diabetic nephropathy Smad1 α-smooth muscle actin BMP4 angiotensin II type IV collagen glomerulosclerosis Src smad1 Id2 ALK

项目摘要

We studied the signaling mechanisms of Smad1-related genes, which play important roles in the process of diabetic nephropathy. We demonstrated that Smad1 is a key transcriptional factor by regulating the expression of type IV collagen (Co14) and α-smooth muscle actin, and plays a critical role for the progression of mesangial matrix expansion in diabetic nephropathy in vivo. Our study also indicates that the amount of urinary Smad1 excretion would be a better diagnostic marker than albuminuria to assess mesangial matrix expansion in diabetic nephropathy. We also demonstrated that AGEs induced BMP4, Smad1, and Col4 mRNA and protein expressions in mesangial cells. TGF-β neutralizing antibody or Noggin (a BMP antagonist) inhibited these inductions. Moreover knockdown of ALK3/6 by using siRNA transfection against each gene blocked the induction. Furthermore, Smad1 and BMP4 were highly expressed in sclerotic regions of diabetic nephropathy mice. These results suggest that the modulation of both TGF-β/Smad1 and BMP4/Smad1 signaling is deeply responsible for initiation and progression of diabetic nephropathy and that blocking of Smad1 signaling pathway may be beneficial for diabetic complications.Angiotensin II (Ang II) is known to play a pivotal role in the development of diabetic nephropathy. However, the precise mechanism of Ang II-mediated effects on diabetic nephropathy is still unknown. We first showed that Ang II increased expression of Smad1, phospho-Smad1, and phospho-Src in vitro and in vivo, and these inductions were inhibited by olmesartan, PP2, a Src tyrosine kinase inhibitor, and overexpression of dominant negative Src. Moreover, addition of siRNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. These results indicate that Ang II can regulate the development of mesangial matrix expansion in the early phase of diabetic nephropathy through Src and Smad1.

本研究对糖尿病肾病发生发展过程中起重要作用的Smad 1相关基因的信号转导机制进行了研究。我们证明Smad 1是一个关键的转录因子，通过调节IV型胶原（Co 14）和α-平滑肌肌动蛋白的表达，在体内糖尿病肾病系膜基质扩张的进展中起关键作用。我们的研究还表明，尿Smad 1排泄量将是一个更好的诊断指标，比白蛋白尿评估系膜基质扩张糖尿病肾病。我们还证明，AGEs诱导系膜细胞BMP 4，Smad 1和Col 4的mRNA和蛋白表达。TGF-β中和抗体或Noggin（BMP拮抗剂）抑制这些诱导。此外，通过使用针对每个基因的siRNA转染来敲低ALK 3/6阻断了诱导。此外，Smad 1和BMP 4在糖尿病肾病小鼠的肾组织中呈高表达。这些结果提示TGF-β/Smad 1和BMP 4/Smad 1信号通路的调节在糖尿病肾病的发生和发展中起重要作用，阻断Smad 1信号通路可能有利于糖尿病并发症的发生和发展，而血管紧张素II（Angiotensin II，Ang II）在糖尿病肾病的发生发展中起重要作用。然而，血管紧张素II介导的糖尿病肾病的确切机制仍然是未知的。我们首先发现，血管紧张素II增加Smad 1，磷酸化Smad 1，磷酸化Src在体外和体内的表达，这些诱导抑制奥美沙坦，PP 2，Src酪氨酸激酶抑制剂，和显性负性Src的过度表达。此外，针对Src的siRNA的加入显著降低了Smad 1的磷酸化和Col 4的合成。提示Ang Ⅱ可通过Src和Smad 1调控糖尿病肾病早期系膜基质扩张的发生发展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of STAT3/Smadl is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis.

STAT3/Smad1 的激活是实验性肾小球肾炎进展为肾小球硬化的关键信号通路。

DOI：
发表时间：
2005
期刊：
J Biol Chem 280
影响因子：
0
作者：
Takahashi T;Kita T;Doi T
通讯作者：
Doi T

糖尿病カレントライブラリー(5)

糖尿病当前图书馆 (5)

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
Inagi R;et al.;Takahashi T;安部秀斉
通讯作者：
安部秀斉

Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis

DOI：
10.1074/jbc.m411064200
发表时间：
2005-02-25
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Takahashi, T;Abe, H;Doi, T
通讯作者：
Doi, T

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

DOI：
10.1038/labinvest.3700400
发表时间：
2006-04-01
期刊：
LABORATORY INVESTIGATION
影响因子：
5
作者：
Matsubara, T;Abe, H;Doi, T
通讯作者：
Doi, T

Angiotensin II-dependent Src and Smadl signaling pathway is crucial for the development of diabetic nephropathy

血管紧张素II依赖性Src和Smadl信号通路对于糖尿病肾病的发生至关重要

DOI：
发表时间：
2006
期刊：
Lab Invest Vol.86No.1
影响因子：
0
作者：
Mima A;Matsubara T;Arai H;Abe H;Nagai K;Kanamori H;Fukatsu A;Salant DJ;Fukatsu A;Kita T;Doi T
通讯作者：
Doi T