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Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis

Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function p...

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Autores principales: Cai, Zhaoxian, Wu, Xiaotian, Song, Zijun, Sun, Shumin, Su, Yunxing, Wang, Tianyi, Cheng, Xihao, Yu, Yingying, Yu, Chao, Chen, En, Chen, Wenteng, Yu, Yongping, Linkermann, Andreas, Min, Junxia, Wang, Fudi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582023/
https://www.ncbi.nlm.nih.gov/pubmed/37848438
http://dx.doi.org/10.1038/s41421-023-00595-3
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author Cai, Zhaoxian
Wu, Xiaotian
Song, Zijun
Sun, Shumin
Su, Yunxing
Wang, Tianyi
Cheng, Xihao
Yu, Yingying
Yu, Chao
Chen, En
Chen, Wenteng
Yu, Yongping
Linkermann, Andreas
Min, Junxia
Wang, Fudi
author_facet Cai, Zhaoxian
Wu, Xiaotian
Song, Zijun
Sun, Shumin
Su, Yunxing
Wang, Tianyi
Cheng, Xihao
Yu, Yingying
Yu, Chao
Chen, En
Chen, Wenteng
Yu, Yongping
Linkermann, Andreas
Min, Junxia
Wang, Fudi
author_sort Cai, Zhaoxian
collection PubMed
description Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4–bound to metformin–iron–NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI.
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spelling pubmed-105820232023-10-19 Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis Cai, Zhaoxian Wu, Xiaotian Song, Zijun Sun, Shumin Su, Yunxing Wang, Tianyi Cheng, Xihao Yu, Yingying Yu, Chao Chen, En Chen, Wenteng Yu, Yongping Linkermann, Andreas Min, Junxia Wang, Fudi Cell Discov Article Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4–bound to metformin–iron–NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI. Springer Nature Singapore 2023-10-17 /pmc/articles/PMC10582023/ /pubmed/37848438 http://dx.doi.org/10.1038/s41421-023-00595-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cai, Zhaoxian
Wu, Xiaotian
Song, Zijun
Sun, Shumin
Su, Yunxing
Wang, Tianyi
Cheng, Xihao
Yu, Yingying
Yu, Chao
Chen, En
Chen, Wenteng
Yu, Yongping
Linkermann, Andreas
Min, Junxia
Wang, Fudi
Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title_full Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title_fullStr Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title_full_unstemmed Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title_short Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis
title_sort metformin potentiates nephrotoxicity by promoting netosis in response to renal ferroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582023/
https://www.ncbi.nlm.nih.gov/pubmed/37848438
http://dx.doi.org/10.1038/s41421-023-00595-3
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