Transforming growth factor-β1 (TGFβ1) has a key role in the development of diabetic nephropathy (DN). However, existing approaches to target TGFβ1 have failed to improve outcomes in clinical trials. Now, Gao et al. suggest that targeting the transcriptional repressor protein YY1 could be a promising therapeutic strategy for DN.
Using a mass spectrometry-based DNA–protein interaction screen in human renal mesangial cells (HRMCs), the researchers identified YY1 as a potential transcriptional regulator of TGFβ1. They found that YY1 was upregulated in high-glucose treated but not in low-glucose treated HRMCs.
Further analyses confirmed that YY1 binds directly to the promoter region of the TGFB1 gene and represses its transcription. Consistent with this finding, overexpression of YY1 reduced the expression of TGFβ1 and downstream proteins in HRMCs, whereas knockout of YY1 had the opposite effect.
In mouse models of DN, expression of YY1 negatively correlated with TGFβ1 expression and the severity of renal fibrosis. Moreover, knockdown of YY1 in glomeruli led to increased expression of TGFβ1 and exacerbated renal fibrosis, whereas overexpression of YY1 suppressed TGFβ1 expression and attenuated the development of DN in mice.
Renal biopsy samples from patients with mild DN had significantly higher glomerular expression of YY1, lower expression of TGFβ1 and less severe glomerulosclerosis than those from patients with severe DN. As the patients had similar diabetes durations, Gao et al. suggest “YY1 may play a renoprotective role by downregulating TGFβ1 in the setting of diabetic pathology”.
Finally, the researchers show that a small molecule, eudesmin, upregulated YY1 in HRMCs and attenuated renal fibrosis by upregulating YY1 in DN mice. They conclude that YY1 is a critical transcriptional suppressor of TGFβ1 and suggest that targeting YY1 using small molecules is a potential novel therapeutic approach for DN.
Gao, P. et al. Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1. Sci. Transl Med. 11, eaaw2050 (2019)
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Carney, E. A novel approach to targeting TGFβ1. Nat Rev Nephrol 15, 730 (2019). https://doi.org/10.1038/s41581-019-0219-3