MiR-122-5p knockdown protects against APAP-mediated liver injury through up-regulating NDRG3
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MiR-122-5p knockdown protects against APAP-mediated liver injury through up-regulating NDRG3 Zhi Yang1 · Weigang Wu2 · Pengcheng Ou1 · Minna Wu1 · Furong Zeng1 · Boping Zhou2 · Shipin Wu1 Received: 28 June 2020 / Accepted: 16 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract MiR-122-5p serves as a novel biomarker for drug-induced liver injury (DILI), but its function in DILI remains unclear. The present study, therefore, explored the function and potential mechanism of miR-122-5p in DILI. Sprague-Dawley (SD) rats were treated with miR-122-5p antagomir, and then DILI was induced in the rats by acetaminophen (APAP). To determine the effect of miR-122-5p on DILI in vivo, liver injury was examined by HE staining and TUNEL assays, and the levels of serum ALT and AST were determined using an automated clinical chemistry analyzer. To further reveal the mechanism of miR-122-5p in DILI, THLE-2 (normal liver cell line) cells were transfected with miR-122-5p mimic and inhibitor, NDRG3, and siNDRG3, and then injured by APAP. The relationship between miR-122-5p and NDRG3 was determined by TargetScan, luciferase reporter assay, and Western blot. The viability and apoptosis of THLE-2 cells were detected by CCK-8 and flow cytometry, respectively. The levels of mRNA and protein in vivo and in vitro were measured by qRT-PCR and Western blot, respectively. APAP induced liver injury and increased the levels of ALT, AST, and miR-122-5p in DILI rats. However, these effects of APAP were attenuated by miR-122-5p antagomir. MiR-122-5p negatively regulated NDRG3 expression. APAP decreased cell viability, apoptosis resistance, and Bcl-w and Bcl-2 levels whereas increased Bax level in THLE-2 cells. However, these effects of APAP on THLE-2 cells were promoted by miR-122-5p up-regulation but inhibited by miR122-5p knockdown. MiR-122-5p knockdown protects against APAP-mediated liver injury through up-regulating NDRG3. Keywords microRNAs · miR-122-5p · NDRG3 · APAP · Drug-induced liver injury
Introduction Drug-induced liver injury (DILI) is a frequent side effect caused by many drugs and involves acute liver failure (ALF) in some cases [1]. DILI accounts for 20% of the ALF cases in China [2]. However, in the Western world, DILI is still the most frequent cause of ALF, accounting for over half
* Boping Zhou [email protected] * Shipin Wu [email protected] 1
Department of Infectious Disease, Shenzhen People’s Hospital, The Second Affiliated Clinical Medical College of Jinan University, No.1017, North Dongmen Road, Luohu District, Shenzhen 518000, Guangdong, China
Department of Infectious Disease, Shenzhen People’s Hospital Longhua Branch, No.101, East Longguan Road, Longhua Street, Longhua District, Shenzhen 518000, Guangdong, China
2
of the ALF cases [3]. A previous report estimated that the incidence of DILI ranged from 13.9 to 19.1 cases in every 100,000 people every year [4]. DILI also represents a remarkable reason for morbidity and mortality [5, 6]. Moreover, in the early stages of drug d
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