Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1

被引：59

作者：

Gao, Pan ^{[1
,11
]}

Li, Liliang ^{[2
]}

Yang, Liu ^{[1
]}

Gui, Dingkun ^{[3
]}

Zhang, Jiarong ^{[4
]}

Han, Junfeng ^{[1
]}

Wang, Jiajia ^{[5
]}

Wang, Niansong ^{[5
]}

Lu, Junxi ^{[1
]}

Chen, Suzhen ^{[1
]}

Hou, Liping ^{[1
]}

Sun, Honglin ^{[1
]}

Xie, Liping ^{[1
]}

Zhou, Jian ^{[1
]}

Peng, Chao ^{[6
]}

Lu, Yan ^{[7
]}

Peng, Xuemei ^{[8
]}

Wang, Cunchuan ^{[8
]}

Miao, Ji ^{[9
]}

Ozcan, Umut ^{[9
]}

Huang, Yu ^{[10
]}

Jia, Weiping ^{[1
]}

Liu, Junli ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Diabet Inst, Dept Endocrinol & Metab,Affiliated Peoples Hosp 6, Shanghai 200032, Peoples R China

[2] Fudan Univ, Dept Forens Med, Sch Basic Med Sci, Shanghai 200032, Peoples R China

[3] Shanghai Jiao Tong Univ, Dept Nephrol, Affiliated Peoples Hosp 6, Shanghai 200032, Peoples R China

[4] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[5] Soochow Univ, Dept Endocrinol, Affiliated Hosp 3, Changzhou 213001, Peoples R China

[6] Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China

[7] Fudan Univ, Dept Endocrinol & Metab, Zhongshan Hosp, Shanghai 200025, Peoples R China

[8] Jinan Univ, Affiliated Hosp 1, Dept Metab & Bariatr Surg, Guangzhou 510632, Guangdong, Peoples R China

[9] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[10] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong 999077, Peoples R China

[11] Fudan Univ, Shanghai Inst Cardiovasc Dis, Zhongshan Hosp, Shanghai 200032, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 510期

基金：

中国国家自然科学基金; 国家自然科学基金重大研究计划; 国家重点研发计划;

关键词：

EXPRESSION; EUDESMIN; NRF2; INHIBITION; ACTIVATION; APOPTOSIS; RECEPTOR; THERAPY; CANCER;

D O I：

10.1126/scitranslmed.aaw2050

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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.

引用

页数：14

共 31 条

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