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Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to A...

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Autores principales: Deng, Hui-Fang, Yue, Lan-Xin, Wang, Ning-Ning, Zhou, Yong-Qiang, Zhou, Wei, Liu, Xian, Ni, Yu-Hao, Huang, Cong-Shu, Qiu, Li-Zhen, Liu, Hong, Tan, Hong-Ling, Tang, Xiang-Lin, Wang, Yu-Guang, Ma, Zeng-Chun, Gao, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873870/
https://www.ncbi.nlm.nih.gov/pubmed/33584308
http://dx.doi.org/10.3389/fphar.2020.624529
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author Deng, Hui-Fang
Yue, Lan-Xin
Wang, Ning-Ning
Zhou, Yong-Qiang
Zhou, Wei
Liu, Xian
Ni, Yu-Hao
Huang, Cong-Shu
Qiu, Li-Zhen
Liu, Hong
Tan, Hong-Ling
Tang, Xiang-Lin
Wang, Yu-Guang
Ma, Zeng-Chun
Gao, Yue
author_facet Deng, Hui-Fang
Yue, Lan-Xin
Wang, Ning-Ning
Zhou, Yong-Qiang
Zhou, Wei
Liu, Xian
Ni, Yu-Hao
Huang, Cong-Shu
Qiu, Li-Zhen
Liu, Hong
Tan, Hong-Ling
Tang, Xiang-Lin
Wang, Yu-Guang
Ma, Zeng-Chun
Gao, Yue
author_sort Deng, Hui-Fang
collection PubMed
description Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.
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spelling pubmed-78738702021-02-11 Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity Deng, Hui-Fang Yue, Lan-Xin Wang, Ning-Ning Zhou, Yong-Qiang Zhou, Wei Liu, Xian Ni, Yu-Hao Huang, Cong-Shu Qiu, Li-Zhen Liu, Hong Tan, Hong-Ling Tang, Xiang-Lin Wang, Yu-Guang Ma, Zeng-Chun Gao, Yue Front Pharmacol Pharmacology Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy. Frontiers Media S.A. 2021-01-21 /pmc/articles/PMC7873870/ /pubmed/33584308 http://dx.doi.org/10.3389/fphar.2020.624529 Text en Copyright © 2021 Deng, Yue, Wang, Zhou, Zhou, Liu, Ni, Huang, Qiu, Liu, Tan, Tang, Wang, Ma and Gao. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/) . 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 Pharmacology
Deng, Hui-Fang
Yue, Lan-Xin
Wang, Ning-Ning
Zhou, Yong-Qiang
Zhou, Wei
Liu, Xian
Ni, Yu-Hao
Huang, Cong-Shu
Qiu, Li-Zhen
Liu, Hong
Tan, Hong-Ling
Tang, Xiang-Lin
Wang, Yu-Guang
Ma, Zeng-Chun
Gao, Yue
Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title_full Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title_fullStr Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title_full_unstemmed Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title_short Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity
title_sort mitochondrial iron overload-mediated inhibition of nrf2-ho-1/gpx4 assisted ali-induced nephrotoxicity
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873870/
https://www.ncbi.nlm.nih.gov/pubmed/33584308
http://dx.doi.org/10.3389/fphar.2020.624529
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