Research ArticleKidney Disease

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

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Science Translational Medicine  18 Sep 2019:
Vol. 11, Issue 510, eaaw2050
DOI: 10.1126/scitranslmed.aaw2050

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A target in diabetic nephropathy

Diabetic nephropathy (DN) is a major cause of kidney failure, but treatments for associated fibrosis and glomerulosclerosis are lacking. Here, Gao and Li et al. showed that Yin Yang 1 (YY1) protein negatively regulates transforming growth factor–β1 (TGFβ1) in human mesangial renal cells (HMRCs) by binding the TGFB1 promoter to repress its transcription. Overexpression and knockdown of Yy1 conversely affected DN progression in diabetic mouse models, and in humans, YY1 expression in glomeruli negatively correlated with TGFβ1 and renal fibrosis. The small molecule eudesmin increased YY1 expression in HMRCs and attenuated renal fibrosis in diabetic mice, demonstrating that YY1 is a potential antifibrotic target in DN.

Abstract

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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