{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:17Z","timestamp":1787027777103,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007658","name":"Baxter Healthcare Corporation","doi-asserted-by":"publisher","award":["Baxter Healthcare Corporation, Grant award"],"award-info":[{"award-number":["Baxter Healthcare Corporation, Grant award"]}],"id":[{"id":"10.13039\/100007658","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007658","name":"Baxter Healthcare Corporation","doi-asserted-by":"publisher","award":["Grant award"],"award-info":[{"award-number":["Grant award"]}],"id":[{"id":"10.13039\/100007658","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Along with infections, ultrafiltration failure due to the toxicity of glucose-containing peritoneal dialysis (PD) solutions is the Achilles\u2019 heel of PD method. Triggered by the protective effect of general control nonderepressible-2 (GCN-2) kinase activation against high-glucose conditions in other cell types, we evaluated whether the same occurs in human peritoneal mesothelial cells. We activated GCN-2 kinase with halofuginone or tryptophanol, and assessed the impact of this intervention on glucose transporter-1, glucose transporter-3, and sodium-glucose cotransporter-1, glucose influx, reactive oxygen species (ROS), and the events that result in glucotoxicity. These involve the inhibition of glyceraldehyde 3-phosphate dehydrogenase and the diversion of upstream glycolytic products to the aldose pathway (assessed by D-sorbitol), the lipid synthesis pathway (assessed by protein kinase C activity), the hexosamine pathway (determined by O-linked \u03b2-N-acetyl glucosamine-modified proteins), and the advanced glycation end products generation pathway (assessed by methylglyoxal). Then, we examined the production of the profibrotic transforming growth factor-\u03b21 (TGF-\u03b21), the pro-inflammatory interleukin-8 (IL-8). Cell apoptosis was assessed by cleaved caspase-3, and mesothelial to mesenchymal transition (MMT) was evaluated by \u03b1-smooth muscle actin protein. High-glucose conditions increased glucose transporters, glucose influx, ROS, all the high-glucose-induced harmful pathways, TGF-\u03b21 and IL-8, cell apoptosis, and MMT. Halofuginone and tryptophanol inhibited all of the above high glucose-induced alterations, indicating that activation of GCN-2 kinase ameliorates glucotoxicity in human peritoneal mesothelial cells, preserves their integrity, and prevents MMT. Whether such a strategy could be applied in the clinic to avoid ultrafiltration failure in PD patients remains to be investigated.<\/jats:p>","DOI":"10.3390\/biom9120832","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T11:16:23Z","timestamp":1575544583000},"page":"832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Activation of General Control Nonderepressible-2 Kinase Ameliorates Glucotoxicity in Human Peritoneal Mesothelial Cells, Preserves Their Integrity, and Prevents Mesothelial to Mesenchymal Transition"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9302-1633","authenticated-orcid":false,"given":"Theodoros","family":"Eleftheriadis","sequence":"first","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Pissas","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Antoniadi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evdokia","family":"Nikolaou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyridon","family":"Golfinopoulos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7564-2724","authenticated-orcid":false,"given":"Vassilios","family":"Liakopoulos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Stefanidis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1053\/j.ajkd.2017.08.028","article-title":"Comparison of Patient Survival Between Hemodialysis and Peritoneal Dialysis Among Patients Eligible for Both Modalities","volume":"71","author":"Wong","year":"2018","journal-title":"Am. 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