MicroRNA-141 binds to the nerve growth factor receptor associated protein 1 gene and restores the erectile function of diabetic rats through down-regulating the nerve growth factor/neurotrophin receptor p75 (NGF/p75NTR) signaling.

Abstract

Erectile dysfunction (ED) is one of the major complications in diabetes mellitus (DM). We have previously reported that the nerve growth factor (NGF)/tyrosine kinase receptor (TrkA) signaling is actively involved in DM-induced ED (DMED). Here, we investigate the effect of micro-RNA-141 (miR-141) on the NGF/p75 neurotrophin receptor (p75NTR) signaling and erectile function of diabetic rats. Sprague-Dawlay (SD) rats were used to establish a DMED model. The dual-luciferase reporter gene assay was first performed to identify the nerve growth factor receptor-associated protein 1 (NGFRAP1) gene as the target gene of miR-141. The regulatory mechanisms underlying miR-141 governing NGFRAP1 in vivo were then validated by modulating the expressions of miR-141 and knocking down NGFRAP1. The expressions of miR-141 were decreased while the expressions of NGFRAP1, NGF, and p75NTR were increased in DMED. miR-141 and downregulation of NGFRAP1, respectively, increased the density of corpus cavernosum smooth muscle and the ratio of intracavernosal pressure (ICP)/mean arterial blood pressure (MAP) and promoted the expression of α-actin and desmin as well. miR-141 also upregulated the expressions of NGFRAP1 in DMED, and knockdown of NGFRAP1 inhibited the productions of NGF and p75NTR. Furthermore, miR-141 suppressed the NGF/p75NTR signaling via binding to NGFRAP1. NGF/p75NTR signaling actively participates in the pathogenesis of DMED. miR-141 binds to NGFRAP1 and restores the erectile function of diabetic rats via downregulation of NGF/p75NTR signaling.