Cargando…

Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway

Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is a...

Descripción completa

Detalles Bibliográficos
Autores principales: Gui, Zeping, Suo, Chuanjian, Wang, Zijie, Zheng, Ming, Fei, Shuang, Chen, Hao, Sun, Li, Han, Zhijian, Tao, Jun, Ju, Xiaobin, Yang, Haiwei, Gu, Min, Tan, Ruoyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076642/
https://www.ncbi.nlm.nih.gov/pubmed/33927720
http://dx.doi.org/10.3389/fimmu.2021.650424
_version_ 1783684723859521536
author Gui, Zeping
Suo, Chuanjian
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Tao, Jun
Ju, Xiaobin
Yang, Haiwei
Gu, Min
Tan, Ruoyun
author_facet Gui, Zeping
Suo, Chuanjian
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Tao, Jun
Ju, Xiaobin
Yang, Haiwei
Gu, Min
Tan, Ruoyun
author_sort Gui, Zeping
collection PubMed
description Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1β, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction.
format Online
Article
Text
id pubmed-8076642
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-80766422021-04-28 Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway Gui, Zeping Suo, Chuanjian Wang, Zijie Zheng, Ming Fei, Shuang Chen, Hao Sun, Li Han, Zhijian Tao, Jun Ju, Xiaobin Yang, Haiwei Gu, Min Tan, Ruoyun Front Immunol Immunology Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1β, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction. Frontiers Media S.A. 2021-04-13 /pmc/articles/PMC8076642/ /pubmed/33927720 http://dx.doi.org/10.3389/fimmu.2021.650424 Text en Copyright © 2021 Gui, Suo, Wang, Zheng, Fei, Chen, Sun, Han, Tao, Ju, Yang, 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
Wang, Zijie
Zheng, Ming
Fei, Shuang
Chen, Hao
Sun, Li
Han, Zhijian
Tao, Jun
Ju, Xiaobin
Yang, Haiwei
Gu, Min
Tan, Ruoyun
Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title_full Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title_fullStr Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title_full_unstemmed Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title_short Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
title_sort impaired atg16l-dependent autophagy promotes renal interstitial fibrosis in chronic renal graft dysfunction through inducing endmt by nf-κb signal pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076642/
https://www.ncbi.nlm.nih.gov/pubmed/33927720
http://dx.doi.org/10.3389/fimmu.2021.650424
work_keys_str_mv AT guizeping impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT suochuanjian impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT wangzijie impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT zhengming impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT feishuang impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT chenhao impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT sunli impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT hanzhijian impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT taojun impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT juxiaobin impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT yanghaiwei impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT gumin impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway
AT tanruoyun impairedatg16ldependentautophagypromotesrenalinterstitialfibrosisinchronicrenalgraftdysfunctionthroughinducingendmtbynfkbsignalpathway