PRMT1-Orchestrated Fibroblast Activation in Renal Fibrosis Induced by TGFß/Smad3 Signaling Pathway

Abstract

TGFβ/Smad3 signaling pathway contributes predominantly to fibroblast activation and epithelial trans-differentiation in diabetic nephrology (DN). Our previous study has demonstrated that protein arginine methyltransferase 1 (PRMT1) mediated glomerular fibrosis in DN via phosphorylation of ERK. However, it is far from clear whether PRMT1 plays an important role in renal fibrosis induced by TGFβ1 signaling pathway. To investigate PRMT1 function, we used AMI-1, a novel inhibitor for PRMT1, in fibroblast both in vitro and in murine unilateral ureteral obstruction (UUO). Immunoblot analysis showed that AMI-1 reduced rat fibroblast cells (NRK-49F) and mouse tubular epithelial cells (mTEC) activation and accumulation of extra cellular matrix(ECM) and phosphorylation of Smad3 induced by serum or TGFβ1 (5ng/ml). The TGFβ1 induced deposited ECM and phosphorous Smad3 synthesis were repressed in NRK-49F transfected with small interfering RNA for PRMT1. Through immunoblot, immunohistochemistry and Masson analysis, UUO induced renal architecture and fibrosis were effectively attenuated by AMI-1 (10mg/kg, intraperitoneal injection once a day). α-SMA and PRMT1 were co-expressed in activated fibroblast in renal glomerular and tubular interstitial induced by UUO in mice and IgA nephrology and diabetic nephrology in human kidneys via dual-immunofluorescence staining. Taken together, our data reveals that AMI-1 presents a restrainable protection on TGFβ1 induced signaling, suggesting that its in-vivo application might extend to the treatment of fibrotic diseases. Disclosure Y. Zhu: None.