Cargando…

Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonst...

Descripción completa

Detalles Bibliográficos
Autores principales: Shi, Yingfeng, Hu, Yan, Wang, Yi, Ma, Xiaoyan, Tang, Lunxian, Tao, Min, Qiu, Andong, Zhuang, Shougang, Liu, Na
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419262/
https://www.ncbi.nlm.nih.gov/pubmed/34497522
http://dx.doi.org/10.3389/fphar.2021.724141
_version_ 1783748710995329024
author Shi, Yingfeng
Hu, Yan
Wang, Yi
Ma, Xiaoyan
Tang, Lunxian
Tao, Min
Qiu, Andong
Zhuang, Shougang
Liu, Na
author_facet Shi, Yingfeng
Hu, Yan
Wang, Yi
Ma, Xiaoyan
Tang, Lunxian
Tao, Min
Qiu, Andong
Zhuang, Shougang
Liu, Na
author_sort Shi, Yingfeng
collection PubMed
description Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.
format Online
Article
Text
id pubmed-8419262
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84192622021-09-07 Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis Shi, Yingfeng Hu, Yan Wang, Yi Ma, Xiaoyan Tang, Lunxian Tao, Min Qiu, Andong Zhuang, Shougang Liu, Na Front Pharmacol Pharmacology Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8419262/ /pubmed/34497522 http://dx.doi.org/10.3389/fphar.2021.724141 Text en Copyright © 2021 Shi, Hu, Wang, Ma, Tang, Tao, Qiu, Zhuang and Liu. 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 Pharmacology
Shi, Yingfeng
Hu, Yan
Wang, Yi
Ma, Xiaoyan
Tang, Lunxian
Tao, Min
Qiu, Andong
Zhuang, Shougang
Liu, Na
Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title_full Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title_fullStr Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title_full_unstemmed Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title_short Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
title_sort blockade of autophagy prevents the development and progression of peritoneal fibrosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419262/
https://www.ncbi.nlm.nih.gov/pubmed/34497522
http://dx.doi.org/10.3389/fphar.2021.724141
work_keys_str_mv AT shiyingfeng blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT huyan blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT wangyi blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT maxiaoyan blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT tanglunxian blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT taomin blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT qiuandong blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT zhuangshougang blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis
AT liuna blockadeofautophagypreventsthedevelopmentandprogressionofperitonealfibrosis