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.

晚期糖基化终末产物诱导 MC 中 BMP4-Smad1 信号通路下游软骨细胞标记蛋白的表达。此外，缺氧还诱导HIF-1和软骨细胞标志物的表达。 SOX9 的过度表达导致软骨细胞标记物的异位表达。观察糖尿病肾病小鼠肾小球中 HIF-1、BMP4 和软骨细胞标志物的表达。 SOX9 与 HIF-1 在糖尿病肾小球中共定位。 BMP4敲入转基因小鼠不仅表现出与DN相似的病理病变，而且在硬化病变中诱导软骨细胞标志物。 HIF-1 和 BMP4 诱导 DN 中 SOX9 的表达以及随后的软骨形成表型变化。结果表明，慢性缺氧应激下MCs转分化为软骨细胞样细胞可能导致DN不可逆的结构变化。

项目成果

Transcription factor 7-like 2(TCF7L2) regulates activin receptor-like kinase 1(ALK1)/ Smad1 pathway for development of diabetic nephropathy

转录因子 7 样 2 (TCF7L2) 调节激活素受体样激酶 1 (ALK1)/Smad1 通路促进糖尿病肾病的发生

• DOI: 10.1007/s10059-010-0109-9
• 发表时间: 2010
• 影响因子: 3.8
• 作者: Araoka T; Abe H; Tominaga T; Mima A; Matsubara T; Murakami T; Kishi S; Nagai K; Doi T
• 通讯作者: Doi T

Recent progress in understanding the molecular pathogenesis of diabetic nephropathy

糖尿病肾病分子发病机制的最新进展

• 发表时间: 2011
• 作者: Abe H

Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy

骨形态发生蛋白 4 信号传导的激活导致类似于糖尿病肾病的肾小球硬化

• DOI: 10.1074/jbc.m110.179382
• 发表时间: 2011
• 影响因子: 4.8
• 作者: Tominaga T; Abe H; Ueda O; Goto C; Nakahara K; Murakami T; Mima A; Nagai K; Araoka T; Kishi S; Fukushima N; Jishage KI; Doi T
• 通讯作者: Doi T

腎疾患の病態形成におけるBMP4・Smad1の役割

BMP4 和 Smad1 在肾脏疾病发病机制中的作用

• 发表时间: 2011
• 作者: 安部秀斉

Sox9 induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy

Sox9 诱导系膜细胞的软骨形成表型并导致晚期糖尿病肾病

• DOI: 10.1074/jbc.m111.244541
• 发表时间: 2011
• 影响因子: 4.8
• 作者: Kishi S; Abe H; Akiyama H; Tominaga T; Murakami T; Mima A; Nagai K; Kishi F; Matsuura M; Matsubara T; Iehara N; Ueda O; Fukushima N; Jishage KI; Doi T.
• 通讯作者: Doi T.