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Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway
Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019825/ https://www.ncbi.nlm.nih.gov/pubmed/33829014 http://dx.doi.org/10.3389/fcell.2021.630412 |
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author | Wang, Jin Sun, Xuefeng Wang, Xu Cui, Shaoyuan Liu, Ran Liu, Jiaona Fu, Bo Gong, Ming Wang, Conghui Shi, Yushen Chen, Qianqian Cai, Guangyan Chen, Xiangmei |
author_facet | Wang, Jin Sun, Xuefeng Wang, Xu Cui, Shaoyuan Liu, Ran Liu, Jiaona Fu, Bo Gong, Ming Wang, Conghui Shi, Yushen Chen, Qianqian Cai, Guangyan Chen, Xiangmei |
author_sort | Wang, Jin |
collection | PubMed |
description | Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3. |
format | Online Article Text |
id | pubmed-8019825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80198252021-04-06 Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway Wang, Jin Sun, Xuefeng Wang, Xu Cui, Shaoyuan Liu, Ran Liu, Jiaona Fu, Bo Gong, Ming Wang, Conghui Shi, Yushen Chen, Qianqian Cai, Guangyan Chen, Xiangmei Front Cell Dev Biol Cell and Developmental Biology Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3. Frontiers Media S.A. 2021-03-22 /pmc/articles/PMC8019825/ /pubmed/33829014 http://dx.doi.org/10.3389/fcell.2021.630412 Text en Copyright © 2021 Wang, Sun, Wang, Cui, Liu, Liu, Fu, Gong, Wang, Shi, Chen, Cai and Chen. 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 | Cell and Developmental Biology Wang, Jin Sun, Xuefeng Wang, Xu Cui, Shaoyuan Liu, Ran Liu, Jiaona Fu, Bo Gong, Ming Wang, Conghui Shi, Yushen Chen, Qianqian Cai, Guangyan Chen, Xiangmei Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title | Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title_full | Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title_fullStr | Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title_full_unstemmed | Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title_short | Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway |
title_sort | grb2 induces cardiorenal syndrome type 3: roles of il-6, cardiomyocyte bioenergetics, and akt/mtor pathway |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019825/ https://www.ncbi.nlm.nih.gov/pubmed/33829014 http://dx.doi.org/10.3389/fcell.2021.630412 |
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