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Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction
Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513042/ https://www.ncbi.nlm.nih.gov/pubmed/36177332 http://dx.doi.org/10.3389/fmed.2022.939149 |
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author | Jiang, Xu-shun Cai, Meng-yao Li, Xun-jia Zhong, Qing Li, Man-li Xia, Yun-feng Shen, Qing Du, Xiao-gang Gan, Hua |
author_facet | Jiang, Xu-shun Cai, Meng-yao Li, Xun-jia Zhong, Qing Li, Man-li Xia, Yun-feng Shen, Qing Du, Xiao-gang Gan, Hua |
author_sort | Jiang, Xu-shun |
collection | PubMed |
description | Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a redox-sensitive transcription factor, is responsible for regulating cellular redox homeostasis. However, the exact role of Nrf2 in dyslipidemia-induced dysfunction of proximal tubule cells is still not fully elucidated. In the present study, we showed that palmitic acid (PA) induced mitochondrial damage, excessive mitochondrial reactive oxygen species (ROS) (mtROS) generation, and cell injury in HK-2 cells. We further found that mtROS generation was involved in PA-induced mitochondrial dysfunction, cytoskeletal damage, and cell apoptosis in HK-2 cells. In addition, we demonstrated that the Nrf2/ARE signaling pathway was activated in PA-induced HK-2 cells and that silencing Nrf2 dramatically aggravated PA-induced mtROS production, mitochondrial damage, cytoskeletal damage and cell apoptosis in HK-2 cells. However, the mitochondrial antioxidant MitoTEMPOL effectively eliminated these negative effects of Nrf2 silencing in HK-2 cells under PA stimulation. Moreover, activation of the Nrf2/ARE signaling pathway with tBHQ attenuated renal injury, significantly reduced mtROS generation, and improved mitochondrial function in rats with HFD-induced obesity. Taken together, these results suggest that the Nrf2/ARE-mediated antioxidant response plays a protective role in hyperlipidemia-induced renal injury by ameliorating mtROS-mediated mitochondrial dysfunction and that enhancing Nrf2 antioxidant signaling provides a potential therapeutic strategy for kidney injury in CKD with hyperlipidemia. |
format | Online Article Text |
id | pubmed-9513042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95130422022-09-28 Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction Jiang, Xu-shun Cai, Meng-yao Li, Xun-jia Zhong, Qing Li, Man-li Xia, Yun-feng Shen, Qing Du, Xiao-gang Gan, Hua Front Med (Lausanne) Medicine Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a redox-sensitive transcription factor, is responsible for regulating cellular redox homeostasis. However, the exact role of Nrf2 in dyslipidemia-induced dysfunction of proximal tubule cells is still not fully elucidated. In the present study, we showed that palmitic acid (PA) induced mitochondrial damage, excessive mitochondrial reactive oxygen species (ROS) (mtROS) generation, and cell injury in HK-2 cells. We further found that mtROS generation was involved in PA-induced mitochondrial dysfunction, cytoskeletal damage, and cell apoptosis in HK-2 cells. In addition, we demonstrated that the Nrf2/ARE signaling pathway was activated in PA-induced HK-2 cells and that silencing Nrf2 dramatically aggravated PA-induced mtROS production, mitochondrial damage, cytoskeletal damage and cell apoptosis in HK-2 cells. However, the mitochondrial antioxidant MitoTEMPOL effectively eliminated these negative effects of Nrf2 silencing in HK-2 cells under PA stimulation. Moreover, activation of the Nrf2/ARE signaling pathway with tBHQ attenuated renal injury, significantly reduced mtROS generation, and improved mitochondrial function in rats with HFD-induced obesity. Taken together, these results suggest that the Nrf2/ARE-mediated antioxidant response plays a protective role in hyperlipidemia-induced renal injury by ameliorating mtROS-mediated mitochondrial dysfunction and that enhancing Nrf2 antioxidant signaling provides a potential therapeutic strategy for kidney injury in CKD with hyperlipidemia. Frontiers Media S.A. 2022-09-13 /pmc/articles/PMC9513042/ /pubmed/36177332 http://dx.doi.org/10.3389/fmed.2022.939149 Text en Copyright © 2022 Jiang, Cai, Li, Zhong, Li, Xia, Shen, Du and Gan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Jiang, Xu-shun Cai, Meng-yao Li, Xun-jia Zhong, Qing Li, Man-li Xia, Yun-feng Shen, Qing Du, Xiao-gang Gan, Hua Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title | Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title_full | Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title_fullStr | Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title_full_unstemmed | Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title_short | Activation of the Nrf2/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
title_sort | activation of the nrf2/are signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513042/ https://www.ncbi.nlm.nih.gov/pubmed/36177332 http://dx.doi.org/10.3389/fmed.2022.939149 |
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