Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

Abstract

Renal fibrosis is the final common pathway leading to end-stage renal disease. Although microRNA (miR) was recently shown to be involved in the development of renal fibrosis, few studies have focused on the effects on renal fibrosis of exogenous miR delivered in an in vivo therapeutic setting. The study reported here investigated the effects of miR-146a delivery using polyethylenimine nanoparticles (PEI-NPs) on renal fibrosis in vivo. PEI-NPs bearing miR-146 or control-miR (nitrogen/phosphate ratio: 6) were injected into the tail vein of a mouse model of renal fibrosis induced by unilateral ureteral obstruction. PEI-NPs bearing miR-146 significantly enhanced miR-146a expression in the obstructed kidney compared with the control group, while inhibiting the renal fibrosis area, expression of alpha-smooth muscle actin, and infiltration of F4/80-positive macrophages into the obstructed kidney. In addition, PEI-NPs bearing miR-146a inhibited the transforming growth factor beta 1–Smad and tumor necrosis factor receptor-associated factor 6–nuclear factor kappa B signaling pathways. Control-miR-PEI-NPs did not show any of these effects. These results suggest that the delivery of miR-146a attenuated renal fibrosis by inhibiting pro-fibrotic and inflammatory signaling pathways and that the delivery of appropriate miRs may be a therapeutic option for preventing renal fibrosis in vivo.

Role of microRNA-146a in regulation of fibrosis in orbital fibroblasts from patients with Graves’ orbitopathy

“…Few studies have explored the relationship between miR-146a and fibrosis; Sonkoly et al 26 reported that miR-146a was significantly overexpressed in psoriatic skin lesions, which is a well-known fibrosing skin disease, compared with normal skin. Morishita et al 10 reported that miR-146a inhibited renal fibrosis by suppressing the profibrotic (Smad4-TGF-β1) and inflammation (TRAF6-NF-κB) signalling pathways. In the present study, we found that miR-146a mimics significantly decreased TGF-β-induced FN, collagen Iα and α-SMA protein production.…”

“…According to previous studies, Smad4 may be a target gene of miR-146a. Morishita et al 10 showed that the exogenous delivery of miR-146a inhibits the TGF-β/Smad and TRAF6-NF-κB signalling pathway, resulting in attenuation of renal fibrosis. The authors suggested that miR-146a may be a therapeutic option for end-stage renal disease.…”

“…Recently, several studies have confirmed that microRNA (miRNA) plays a critical role in the expression of genes associated with the fibrosis of organs such as heart, kidney10 and liver. miRNAs are a family of short non-coding RNAs that regulate gene expression by inhibiting their target messenger RNA (mRNA) 11 12.…”

“…However, few studies have explored the relationship between miR-146a and fibrosis processes 10 26. Recently, Morishita et al 10 reported that miR-146a inhibited renal fibrosis by suppressing profibrotic (Smad4-transforming growth factor-β1 (TGF-β1)) and inflammation (TRAF6-NF-κB) signalling pathways.…”

Efficient Gene Transfer into Chicken Gonads by Combining Transposons with Polyethylenimine

“…PEI, a highly water-soluble cationic polymer, has been widely used for nonviral transfection of DNA and RNA in vitro and in vivo (Lu et al, 2015;Lungwitz et al, 2005;Morishita et al, 2015;Sramkova et al, 2014), and the advantage of PEI over other polycations is that it combines strong DNA compaction capacity with an intrinsic endosomolytic activity (Tang & Szoka, 1997). PEI has two structural forms, linear and branched, with various molecular masses (Fischer et al, 1999;Huh et al, 2007).…”