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Pharmacol."],"abstract":"<jats:p><jats:bold>Background and aims:<\/jats:bold> Renal damage in severe coronavirus disease 2019 (COVID-19) is highly associated with mortality. Finding relevant therapeutic candidates that can alleviate it is crucial. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have been shown to be harmless to COVID-19 patients, but it remains elusive whether ACEIs\/ARBs have protective benefits to them. We wished to determine if ACEIs\/ARBs had a protective effect on the renal damage associated with COVID-19, and to investigate the mechanism.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We used the envelope (E) protein of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to induce COVID-19-like multiple organ damage and observed renal fibrosis. We induced the epithelial\u2013mesenchymal transformation of HK-2 cells with E protein, and found that olmesartan could alleviate it significantly. The protective effects of olmesartan on E protein-induced renal fibrosis were evaluated by renal-function assessment, pathologic alterations, inflammation, and the TGF-\u03b21\/Smad2\/3 signaling pathway. The distribution of high-mobility group box (HMGB)1 was examined after stimulation with E protein and olmesartan administration.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> E protein stimulated HMGB1 release, which triggered the immune response and promoted activation of TGF-\u03b21\/Smad2\/3 signaling: both could lead to renal fibrosis. Olmesartan regulated the distribution of HMGB1 under E protein stimulation. Olmesartan inhibited the release of HMGB1, and reduced the inflammatory response and activation of TGF-\u03b21\/Smad2\/3 signaling. Olmesartan increased the cytoplasmic level of HMGB1 to promote the autophagic degradation of TGF-\u03b21, thereby alleviating fibrosis further.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Olmesartan alleviates E protein-induced renal fibrosis by regulating the release of HMGB1 and its mediated autophagic degradation of TGF-\u03b21.<\/jats:p>","DOI":"10.3389\/fphar.2023.1187818","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T14:36:44Z","timestamp":1684161404000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Olmesartan alleviates SARS-CoV-2 envelope protein induced renal fibrosis by regulating HMGB1 release and autophagic degradation of TGF-\u03b21"],"prefix":"10.3389","volume":"14","author":[{"given":"Shilin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zanzhe","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengling","family":"Ning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuetao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiangang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxue","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1146\/annurev-immunol-030409-101323","article-title":"HMGB1 is a therapeutic target for sterile inflammation and infection","volume":"29","author":"Andersson","year":"2011","journal-title":"Annu. 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