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

Abstract

Yoshiyuki Morishita,1 Toshimi Imai,1 Hiromichi Yoshizawa,1 Minami Watanabe,1 Kenichi Ishibashi,2 Shigeaki Muto,1 Daisuke Nagata1 1Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, 2Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan 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. Keywords: miR, end-stage renal disease, pro-fibrotic signaling pathway, inflammatory signaling pathway