MiR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1

Wenqiang Tao,Fen Liu,Hui Zhan,Jianguo Zhang,Shangmiao Fu,Kejian Qian

doi:10.3389/fmolb.2021.789927

Abstract

Renal ischemia-reperfusion (IR) is frequently observed in patients who are critically ill, yet there are no reliable or effective approaches for the treatment of this condition. Ferroptosis, a form of programmed cell death, is regulated by key genes such as glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HMOX1) and participates in the injury of renal tubular epithelial cells during IR. This study aimed to investigate the miRNA-mRNA regulatory networks involved in ferroptosis following renal IR. Using bioinformatics analysis, HMOX1 was found to be significantly upregulated during the early stages of renal IR injury, and microRNA-3587 (miR-3587) was identified as a putative regulator of HMOX1. When a miR-3587 inhibitor was applied in a hypoxia-reoxygenation (HR) model system using renal tubular epithelial cells, HO-1 protein (encoded by HMOX1) expression was significantly increased relative to that observed in the HR group, with concomitant increases in GPX4 protein levels, enhanced cell viability, a reduction in malondialdehyde content, decreased Fe2+ level, and the restoration of normal mitochondrial membrane potential. Transmission electron microscopy showed a reduced or absent mitochondrial crest and a damaged mitochondrial outer membrane. Targeting of HMOX1 by miR-3587 was confirmed by luciferase reporter gene assay. In conclusion, these preliminary results indicate that inhibition of miR-3587 promotes HO-1 upregulation, thereby protecting renal tissues from IR-induced ferroptosis.

Highlights

Renal ischemia-reperfusion (IR) is a serious clinical condition that is often encountered in critically ill patients such as those that have undergone major surgery, resuscitation following cardiac arrest, and microcirculation recanalization aftershock, resulting in acute kidney injury (AKI) (Beach et al, 2020)
We showed, for the first time, that miR-3587 targets heme miR-3587 Inhibition Attenuates Renal Ischemia-Reperfusion oxygenase-1 (HMOX1), and preliminary in vitro HR model analyses confirmed that miR-3587 inhibition was sufficient to suppress ferroptosis in renal tubular epithelial cells by promoting HO-1 expression
HMOX1 expression in the GSE58438, GSE27274, GSE3219, and GSE9943 datasets is shown in Table 1 and Figures 3A–D. These analyses revealed that HMOX1 expression rose miR-3587 Inhibition Attenuates Renal Ischemia-Reperfusion significantly within 3–8 h after reperfusion, before declining significantly at 24 h post-reperfusion

Summary

Introduction

Renal ischemia-reperfusion (IR) is a serious clinical condition that is often encountered in critically ill patients such as those that have undergone major surgery, resuscitation following cardiac arrest, and microcirculation recanalization aftershock, resulting in acute kidney injury (AKI) (Beach et al, 2020). Ferroptosis, a recently defined form of regulated cell death, is driven by the iron-dependent peroxidation of membrane lipids (Dixon et al, 2012). Glutathione peroxidase 4 (GPX4) and heme miR-3587 Inhibition Attenuates Renal Ischemia-Reperfusion oxygenase-1 (HMOX1), the key genes of ferroptosis, regulate ferroptosis by controlling the state of lipid peroxidation and the level of iron [(Yang et al, 2014; Tang et al, 2021)]. The ferroptosis inhibitor XJB-5-131 is able to protect against renal tubular epithelial cell death and consequent kidney injury in a mouse renal IR model (Zhao et al, 2020)

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