Protein Arginine Methyltransferase 1 mediates Renal Fibroblast Activation and fibrogenesis through activation of Smad3 signaling.

In this study, we observed that PRMT1 and its specific epigenetic marker, asymmetric di-methylated histone 4 arginine 3 (H4R3Me2a), were highly expressed in cultured renal interstitial fibroblasts. Treatment of PRMT1 with AMI-1, a selective inhibitor of PRMT1, or silencing PRMT1 with a small interfering RNA inhibited serum- and transforming growth factor beta1 (TGFβ1)-induced expression of α-smooth muscle actin (α-SMA) and collagen 1, two hallmarks of renal fibroblast activation, in a dose- and time-dependent manner. In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), PRMT1 expression and H4R3Me2a were also upregulated, which was coincident with increased expression of α-SMA, collagen I and fibronectin. Administration of AMI-1 reduced RPMT1 and H4R3Me2a expression, attenuated extracellular matrix protein deposition, and inhibited renal fibroblast activation and proliferation. Moreover, AMI-1 treatment inhibited Smad3 phosphorylation and TGF beta receptor I expression, but prevented Smad7 downregulation both in the kidney following UUO injury and in cultured renal interstitial fibroblasts exposed to TGF beta1. Collectively, these results demonstrate that PRMT1 may mediate renal fibroblast activation and renal fibrosis development through activation of the TGF beta/Smad3 signaling pathway. They also suggest that PRMT1 inhibition may be a potential therapeutic approach for the treatment of fibrotic kidney disease. PMID: 31813251 [Pub...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research