MiR-381-3p knockdown improves intestinal epithelial proliferation and barrier function after intestinal ischemia/reperfusion injury by targeting nurr1

Liwei Liu,Dongcheng Feng,Zhenlu Li,Su Zhang,Jihong Yao,Guo Zu,Wasim Qasim,Yang Li,Huizhi Zeng,Tong Li,Xiaofeng Tian

doi:10.1038/s41419-018-0450-z

Abstract

Impairment in gut barrier function induced by intestinal ischemia/reperfusion (I/R) injury is associated with high morbidity and mortality. Intestinal barrier function requires the tight coordination of epithelial migration, proliferation and differentiation. We previously observed that nuclear receptor-related protein 1 (nurr1)-mediated proliferative pathway was impaired in intestinal I/R injury. Here, we aimed to assess the effect of nurr1 on intestinal barrier function and to evaluate microRNA (miRNA)-nurr1-mediated restoration of intestinal barrier function in intestinal I/R injury. We induced an in vivo intestinal I/R injury mouse model by clamping and then releasing the superior mesenteric artery. We also performed an in vitro study in which we exposed Caco-2 and IEC-6 cells to hypoxia/reoxygenation (H/R) conditions to stimulate intestinal I/R injury. Our results demonstrated that nurr1 regulated intestinal epithelial development and barrier function after intestinal I/R injury. miR-381-3p, which directly suppressed nurr1 translation, was identified by microarray and bioinformatics analysis. miR-381-3p inhibition enhanced intestinal epithelial proliferation and barrier function in vitro and in vivo and also attenuated remote organ injury and improved survival. Importantly, nurr1 played an indispensable role in the protective effect of miR-381-3p inhibition. Collectively, these findings show that miR-381-3p inhibition mitigates intestinal I/R injury by enhancing nurr1-mediated intestinal epithelial proliferation and barrier function. This discovery may lead to the development of therapeutic interventions for intestinal I/R injury.

Highlights

The damage sustained by ischemic intestinal tissue as a result of the activation of vicious cascades during the restoration of blood flow is known as intestinal ischemia/ reperfusion (I/R) injury
We previously found that modulating nurr[1] expression improves epithelial proliferation after intestinal I/R injury[12]
We investigated the effect of miR-381-3p agomir (miR-381)-3p on intestinal epithelial cells exposed to H/R injury and the involvement of nurr[1] signaling in this effect. miR-381-3p inhibition elevated Ki-67-labeled cell proliferation under H/R conditions (Fig. 3a)

Summary

Introduction

The damage sustained by ischemic intestinal tissue as a result of the activation of vicious cascades during the restoration of blood flow is known as intestinal ischemia/ reperfusion (I/R) injury. Official journal of the Cell Death Differentiation Association. It has been reported that several nuclear receptors improved intestinal epithelial development and barrier function after injury[7,8,9]. Nuclear receptor-related protein 1 (nurr1), an orphan nuclear receptor, is a well-known transcription factor that participates in several cellular development processes, such as proliferation, differentiation and apoptosis[10,11]. We previously found that modulating nurr[1] expression improves epithelial proliferation after intestinal I/R injury[12]. Increased epithelial cell proliferation contributes to enhance intestinal epithelial barrier function[13,14]. The effect of nurr[1] on epithelial barrier function after intestinal I/R injury, as well as the mechanism by which nurr[1] is modulated, require further investigation

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