{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:36:02Z","timestamp":1792672562329,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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-\u03b2\/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-\u03baB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of \u03b2-catenin signal. In addition, TGF-\u03b21 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome <jats:italic>in vitro<\/jats:italic>. Exposure of HPMCs to TGF-\u03b21 resulted in the induction of EMT and activation of TGF-\u03b2\/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-\u03b21. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.<\/jats:p>","DOI":"10.3389\/fphar.2021.724141","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T06:19:20Z","timestamp":1629699560000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Yingfeng","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lunxian","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andong","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shougang","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41419-020-2419-y","article-title":"Autophagy Inhibition Potentiates the Anti-EMT Effects of Alteronol through TGF-\u03b2\/Smad3 Signaling in Melanoma Cells","volume":"11","author":"Bao","year":"2020","journal-title":"Cell Death Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1080\/15548627.2015.1034409","article-title":"Essential Role for the ATG4B Protease and Autophagy in Bleomycin-Induced Pulmonary Fibrosis","volume":"11","author":"Cabrera","year":"2015","journal-title":"Autophagy"},{"key":"B3","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/35000025","article-title":"The Transcription Factor Snail Controls Epithelial-Mesenchymal Transitions by Repressing E-Cadherin Expression","volume":"2","author":"Cano","year":"2000","journal-title":"Nat. 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