Protein Arginine Methyltransferase 1-mediated Histone H4R3 Dimethyl Asymmetric enhances Epidermal Growth Factor Receptor signaling to promote Peritoneal Fibrosis.

Abstract

Peritoneal fibrosis (PF) is regarded as one of the major complications of peritoneal dialysis (PD) and is still lack of efficacious clinical interventions to address this issue. Previous publications have indicated that protein arginine methyltransferase 1 (PRMT1) is involved in the pathological process of various diseases. However, the role of PRMT1 in the development of PF remains to be elucidated. In the present study, we demonstrate that PRMT1 is highly expressed in the peritoneum and dialysis effluent of long-term PD patients, and that there is a positive correlation between PRMT1 and the hallmarks of fibrosis in human peritoneal specimens. Our results further demonstrate that the genetic depletion or pharmacological inhibition of PRMT1 has the potential to reduce extracellular matrix deposition and alleviate PF caused by high-glucose peritoneal dialysis fluid (HG-PDF) in murine models. In addition, silencing or pharmacological inhibition of PRMT1 could also reduce the epithelial-to-mesenchymal (EMT) phenotypic change caused by TGF-β1 in vitro. The use of RNA sequencing facilitated the identification of the epidermal growth factor receptor (EGFR) as a target of PRMT1 in PF. Furthermore, the reduction of PRMT1 levels, achieved through either genetic depletion or pharmacological inhibition, results in the deactivation of EGFR downstream signaling pathways. Our findings uncover a novel mechanism by which PRMT1-mediated H4R3me2a activates the EGFR and its associated downstream signaling pathways in the context of PF. Consequently, these findings imply that PRMT1 may serve as a valuable diagnostic or therapeutic target for PF.