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Title: MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism

Abstract

Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3′-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-inducedmore » oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury. - Highlights: • miR-140-5p expression was up-regulated in Cisplatin induced AKI. • miR-140-5p directly targeted the 3′-UTR of Nrf2 mRNA. • miR-140-5p activated the Nrf2/ARE signaling pathway and served as an early protective response against oxidative stress.« less

Authors:
; ; ; ; ; ;  [1];  [2];  [1]
  1. Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China)
  2. Research center for experimental medicine of Ruijin Hospital, Shanghai (China)
Publication Date:
OSTI Identifier:
22738187
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 360; Journal Issue: 2; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; BIOLOGICAL STRESS; ECR HEATING; INJURIES; KIDNEYS; LACTATE DEHYDROGENASE; MESSENGER-RNA; MICE; OXIDATION; SUPEROXIDE DISMUTASE

Citation Formats

Liao, Weitang, Fu, Zongjie, Zou, Yanfang, Wen, Dan, Ma, Hongkun, Zhou, Fangfang, Chen, Yongxi, Zhang, Mingjun, and Zhang, Wen. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.09.019.
Liao, Weitang, Fu, Zongjie, Zou, Yanfang, Wen, Dan, Ma, Hongkun, Zhou, Fangfang, Chen, Yongxi, Zhang, Mingjun, & Zhang, Wen. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism. United States. doi:10.1016/J.YEXCR.2017.09.019.
Liao, Weitang, Fu, Zongjie, Zou, Yanfang, Wen, Dan, Ma, Hongkun, Zhou, Fangfang, Chen, Yongxi, Zhang, Mingjun, and Zhang, Wen. Wed . "MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism". United States. doi:10.1016/J.YEXCR.2017.09.019.
@article{osti_22738187,
title = {MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism},
author = {Liao, Weitang and Fu, Zongjie and Zou, Yanfang and Wen, Dan and Ma, Hongkun and Zhou, Fangfang and Chen, Yongxi and Zhang, Mingjun and Zhang, Wen},
abstractNote = {Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3′-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury. - Highlights: • miR-140-5p expression was up-regulated in Cisplatin induced AKI. • miR-140-5p directly targeted the 3′-UTR of Nrf2 mRNA. • miR-140-5p activated the Nrf2/ARE signaling pathway and served as an early protective response against oxidative stress.},
doi = {10.1016/J.YEXCR.2017.09.019},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 360,
place = {United States},
year = {2017},
month = {11}
}