YY1: A novel therapeutic target for diabetic nephropathy orchestrated renal fibrosis

Background: Renal fibrosis promotes the development of diabetic nephropathy (DN). A growing number of studies have reported that Yin Yang 1 (YY1), which is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of many diseases, such as pulmonary fibrosis, hepatic steatosis and cancer. Methods: We detected the expression of YY1 under various glucose concentration and time gradient conditions. Rapamycin was used to verify the mTORC1/p70S6K/YY1 signaling pathway in HK-2 cells. We used db/db mice to examine the connection between renal fibrosis and YY1. A luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to identify whether YY1 directly regulated alpha-SMA by binding to the alpha-SMA promoter. RNA silencing and overexpression were performed by using a YY1 expression/knockdown plasmid to investigate the function of YY1 in renal fibrosis of DN. Results: YY1 expression and subsequent nuclear translocalion were upregulated in a glucose- and time-dependent manner via the mTORC1/p70SEK signaling pathway in HK-2 cells. YY1 expression and nuclear translocation was significantly upregulated in db/db mice. Furthermore, YY1 upregulated alpha-SMA expression and activity in high-glucose-cultured HK-2 cells. Overexpression of YY1 promoted renal fibrosis in db/m mice mainly by upregulating alpha-SMA expression and inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, downregulation of YY1 reversed renal fibrosis by improving EMT in vivo and in vitro. Conclusions: These results reveal that upregulation of YY1 plays a critical role in HG-induced deregulation of EMT-associated protein expression, which finally results in renal fibrosis of DN. Therefore, decreasing YY1 expression might represent a new therapeutic target for diabetic nephropathy-induced renal fibrosis. (C) 2019 Elsevier Inc. All rights reserved.