Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGF beta 1
Publication in refereed journal

香港中文大學研究人員

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摘要Transforming growth factor-beta 1 (TGF beta 1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGF beta 1 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 TGF beta 1 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.
著者Pan GAO, Liliang LI, Liu YANG, 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 OZCAN, Yu HUANG, Weiping JIA, Junli LIU
期刊名稱Science Translational Medicine
出版年份2019
月份9
日期18
卷號11
期次510
出版社AMER ASSOC ADVANCEMENT SCIENCE
文章號碼eaaw2050
國際標準期刊號1946-6234
電子國際標準期刊號1946-6242
語言英式英語
Web of Science 學科類別Cell Biology;Medicine, Research & Experimental;Cell Biology;Research & Experimental Medicine

上次更新時間 2020-25-10 於 00:43