PRMT1-mediated BRD4 arginine methylation and phosphorylation promote partial epithelial–mesenchymal transformation and renal fibrosis

Abstract

Bromodomain-containing protein 4 (BRD4) plays a vital role in fibrosis of various organs. However, the underlying mechanism of BRD4 in renal fibrosis remains unclear. To construct in vitro and in vivo models of renal fibrosis, TCMK-1 cells were subjected to TGF-β1 treatment and mice were subjected to UUO surgery and adenine induction. IP assay was used for arginine asymmetric dimethylation (ADMA) level, ubiquitination degradation of Snail, and acetylation level of Snail test. Co-IP was used to validate the interactions of BRD4, protein arginine methyltransferase-1 (PRMT1), and Snail. HE staining and Masson staining were used for morphological examination of renal tissue. BRD4 was abnormally overexpressed during renal fibrosis. TGF-β1-induced fibrosis and partial epithelial–mesenchymal transition (pEMT) could be inhibited by BRD4 silencing. PRMT1 mediated ADMA level of BRD4 to enhance BRD4 phosphorylation and its protein stability. Snail protein degradation was attenuated by BRD4 overexpression in an acetylation-dependent manner in TCMK-1 cells. Furthermore, PRMT1 inhibitor abolished BRD4 overexpression-induced fibrosis and pEMT in TGF-β1-treated TCMK-1 cells and Snail overexpression reversed BRD4 silencing-induced inhibition of fibrosis and pEMT. What's more, the reduction of BRD4 arginine methylation inhibited BRD4 phosphorylation and Snail expression to alleviate renal fibrosis in UUO surgery and adenine induction mice. Collectively, PRMT1-mediated BRD4 arginine methylation and phosphorylation promoted pEMT and renal fibrosis through regulation of Snail expression.