Molecular mechanisms for irreversible phenotypic changes leading to renal failure in chronic kidney diseases.

导致慢性肾脏疾病肾衰竭的不可逆表型变化的分子机制。

• 批准号: 21591033
• 负责人: ABE Hideharu
• 金额: $ 2.91万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591033/
• 关键词: 糖尿病性腎症; Sox9; Smad1; BMP4; 軟骨細胞様形質変化; 不可逆的腎機能低下; ALK3/6; Scleraxis; HIF1; ALK3; 6

Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of HIF-1, and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of chondrocyte markers. Glomerular expressions of HIF-1, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. SOX9 was colocalized with HIF-1 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. HIF-1 and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.

晚期糖基化终产物诱导MC中BMP 4-Smad 1信号通路下游软骨细胞标志蛋白的表达。此外，缺氧还诱导HIF-1和软骨细胞标志物的表达。SOX 9的过表达引起软骨细胞标志物的异位表达。观察糖尿病肾病小鼠肾小球中HIF-1、BMP 4和软骨细胞标志物的表达。SOX 9与HIF-1在糖尿病肾小球中共定位。BMP-4基因敲入转基因小鼠不仅表现出与DN相似的病理学改变，而且在软骨病变中诱导出软骨细胞标志物。HIF-1和BMP-4诱导SOX 9表达和随后的DN软骨形成表型改变。结果提示，慢性低氧应激下MC向软骨样细胞的转分化可能导致DN发生不可逆的结构改变。

项目成果

Overexpression of Smad1 Causes Remarkable Glomerulosclerosis in Diabetic Mice

Smad1 过度表达导致糖尿病小鼠出现显着的肾小球硬化

• 发表时间: 2010
• 作者: Takeshi Matsubara;Hideharu Abe;Otoya Ueda;Kou-ichi Jishage;Akira Mima;Chisato Goto;Tatsuya Tominaga;Makoto Araki;Kazuo Torikoshi;Kojiro Nagai;Noriyuki Iehara;Atsushi Fukatsu;Naoshi Fukushima;Hidenori Arai;Toshio Doi
• 通讯作者: Toshio Doi

Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in Glomerulonephritis

• DOI: 10.1159/000321366
• 发表时间: 2010-01-01
• 期刊: AMERICAN JOURNAL OF NEPHROLOGY
• 影响因子: 4.2
• 作者: Murakami, Taichi;Abe, Hideharu;Doi, Toshio
• 通讯作者: Doi, Toshio

Chondrogenic phenotypic change contributes to the irreversible progression of the diabetic nephropathy

软骨表型变化导致糖尿病肾病的不可逆进展

• 发表时间: 2010
• 作者: Kishi S;Abe H;Murakami T;Tominaga T;Nagai K;Mima A;Doi T
• 通讯作者: Doi T

Chondrogenic Potential of Mesangial Cells in Diabetic Nephropathy

糖尿病肾病肾小球系膜细胞的软骨形成潜力

• 发表时间: 2009
• 作者: Kishi S;Abe H;Akiyama H;Doi T
• 通讯作者: Doi T

糖尿病性腎症の分子病態-BMP4-Smad1シグナル

糖尿病肾病的分子病理-BMP4-Smad1信号

• 发表时间: 2011
• 作者: Nagata S;Hatakeyama K;Asami M;Tokashiki M;Hibino H;Nishiuchi Y;Kuwasako K;Kato J;Asada Y;Kitamura K;Michio Shimabukuro;Yang SS;安部秀斉
• 通讯作者: 安部秀斉