Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-05-01
|
Series: | Ecotoxicology and Environmental Safety |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S014765132100169X |
id |
doaj-c46bf4f7601249b39e6124579ae60fe0 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wenxuan Dong Gang Liu Kanglei Zhang Yun Tan Hui Zou Yan Yuan Jianhong Gu Ruilong Song Jiaqiao Zhu Zongping Liu |
spellingShingle |
Wenxuan Dong Gang Liu Kanglei Zhang Yun Tan Hui Zou Yan Yuan Jianhong Gu Ruilong Song Jiaqiao Zhu Zongping Liu Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway Ecotoxicology and Environmental Safety Cadmium Oxidative stress Autophagy Kidney Nrf2 |
author_facet |
Wenxuan Dong Gang Liu Kanglei Zhang Yun Tan Hui Zou Yan Yuan Jianhong Gu Ruilong Song Jiaqiao Zhu Zongping Liu |
author_sort |
Wenxuan Dong |
title |
Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway |
title_short |
Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway |
title_full |
Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway |
title_fullStr |
Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway |
title_full_unstemmed |
Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway |
title_sort |
cadmium exposure induces rat proximal tubular cells injury via p62-dependent nrf2 nucleus translocation mediated activation of ampk/akt/mtor pathway |
publisher |
Elsevier |
series |
Ecotoxicology and Environmental Safety |
issn |
0147-6513 |
publishDate |
2021-05-01 |
description |
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5′ AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally. |
topic |
Cadmium Oxidative stress Autophagy Kidney Nrf2 |
url |
http://www.sciencedirect.com/science/article/pii/S014765132100169X |
work_keys_str_mv |
AT wenxuandong cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT gangliu cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT kangleizhang cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT yuntan cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT huizou cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT yanyuan cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT jianhonggu cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT ruilongsong cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT jiaqiaozhu cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway AT zongpingliu cadmiumexposureinducesratproximaltubularcellsinjuryviap62dependentnrf2nucleustranslocationmediatedactivationofampkaktmtorpathway |
_version_ |
1721513039501459456 |
spelling |
doaj-c46bf4f7601249b39e6124579ae60fe02021-04-23T06:16:37ZengElsevierEcotoxicology and Environmental Safety0147-65132021-05-01214112058Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathwayWenxuan Dong0Gang Liu1Kanglei Zhang2Yun Tan3Hui Zou4Yan Yuan5Jianhong Gu6Ruilong Song7Jiaqiao Zhu8Zongping Liu9College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of China; Corresponding authors at: College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China.College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of ChinaCollege of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People’s Republic of China; Corresponding authors at: College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People’s Republic of China.Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5′ AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally.http://www.sciencedirect.com/science/article/pii/S014765132100169XCadmiumOxidative stressAutophagyKidneyNrf2 |