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Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic...

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Autores principales: Gui, Zeping, Suo, Chuanjian, Tao, Jun, Wang, Zijie, Zheng, Ming, Fei, Shuang, Chen, Hao, Sun, Li, Han, Zhijian, Ju, Xiaobing, Zhang, Hengcheng, Gu, Min, Tan, Ruoyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818677/
https://www.ncbi.nlm.nih.gov/pubmed/35140705
http://dx.doi.org/10.3389/fimmu.2021.753412
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author Gui, Zeping
Suo, Chuanjian
Tao, Jun
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Ju, Xiaobing
Zhang, Hengcheng
Gu, Min
Tan, Ruoyun
author_facet Gui, Zeping
Suo, Chuanjian
Tao, Jun
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Ju, Xiaobing
Zhang, Hengcheng
Gu, Min
Tan, Ruoyun
author_sort Gui, Zeping
collection PubMed
description Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo. To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR’s effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis.
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spelling pubmed-88186772022-02-08 Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α Gui, Zeping Suo, Chuanjian Tao, Jun Wang, Zijie Zheng, Ming Fei, Shuang Chen, Hao Sun, Li Han, Zhijian Ju, Xiaobing Zhang, Hengcheng Gu, Min Tan, Ruoyun Front Immunol Immunology Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo. To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR’s effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis. Frontiers Media S.A. 2022-01-24 /pmc/articles/PMC8818677/ /pubmed/35140705 http://dx.doi.org/10.3389/fimmu.2021.753412 Text en Copyright © 2022 Gui, Suo, Tao, Wang, Zheng, Fei, Chen, Sun, Han, Ju, Zhang, Gu and Tan 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 Immunology
Gui, Zeping
Suo, Chuanjian
Tao, Jun
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Ju, Xiaobing
Zhang, Hengcheng
Gu, Min
Tan, Ruoyun
Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title_full Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title_fullStr Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title_full_unstemmed Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title_short Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only via Inducing Autophagy but Also via Stabilizing IκB-α
title_sort everolimus alleviates renal allograft interstitial fibrosis by inhibiting epithelial-to-mesenchymal transition not only via inducing autophagy but also via stabilizing iκb-α
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818677/
https://www.ncbi.nlm.nih.gov/pubmed/35140705
http://dx.doi.org/10.3389/fimmu.2021.753412
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