心理压抑
糖尿病肾病
医学
转化生长因子
糖尿病
癌症研究
病理
生物
肾病
药理学
内科学
内分泌学
基因表达
基因
生物化学
作者
Pan Gao,Liliang Li,Yang Liu,Dingkun Gui,Jiarong Zhang,Junfeng Han,Jiajia Wang,Niansong Wang,Junxi Lu,Suzhen Chen,Liping Hou,Honglin Sun,Liping Xie,Jian Zhou,Chao Peng,Yan Lu,Xuemei Peng,Cunchuan Wang,Ji Miao,Umut Özcan,Yü Huang,Weiping Jia,Junli Liu
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2019-09-18
卷期号:11 (510)
被引量:51
标识
DOI:10.1126/scitranslmed.aaw2050
摘要
Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.
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