{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:03:48Z","timestamp":1791302628444,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T00:00:00Z","timestamp":1605225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grants funded by the Korea government","award":["2017R1A6A3A04011473"],"award-info":[{"award-number":["2017R1A6A3A04011473"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Podocyte injury inevitably results in leakage of proteins from the glomerular filter and is vital in the pathogenesis of diabetic nephropathy (DN). The underlying mechanisms of podocyte injury facilitate finding of new therapeutic targets for DN treatment and prevention. Tangeretin is an O-polymethoxylated flavone present in citrus peels with anti-inflammatory and antioxidant properties. This study investigated the renoprotective effects of tangeretin on epithelial-to-mesenchymal transition-mediated podocyte injury and fibrosis through oxidative stress and hypoxia caused by hyperglycemia. Mouse podocytes were incubated in media containing 33 mM glucose in the absence and presence of 1\u201320 \u03bcM tangeretin for up to 6 days. The in vivo animal model employed db\/db mice orally administrated with 10 mg\/kg tangeretin for 8 weeks. Non-toxic tangeretin inhibited glucose-induced expression of the mesenchymal markers of N-cadherin and \u03b1-smooth muscle actin in podocytes. However, the reduced induction of the epithelial markers of E-cadherin and P-cadherin was restored by tangeretin in diabetic podocytes. Further, tangeretin enhanced the expression of the podocyte slit diaphragm proteins of nephrin and podocin down-regulated by glucose stimulation. The transmission electron microscopic images revealed that foot process effacement and loss of podocytes occurred in diabetic mouse glomeruli. However, oral administration of 10 mg\/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of slit junction and adherenes junction proteins. Glucose enhanced ROS production and HIF-1\u03b1 induction in podocytes, leading to induction of oxidative stress and hypoxia. Similarly, in diabetic glomeruli reactive oxygen species (ROS) production and HIF-1\u03b1 induction were observed. Furthermore, hypoxia-evoking cobalt chloride induced epithelial-to-mesenchymal transition (EMT) process and loss of slit diaphragm proteins and junction proteins in podocytes, which was inhibited by treating submicromolar tangeretin. Collectively, these results demonstrate that tangeretin inhibited podocyte injury and fibrosis through blocking podocyte EMT caused by glucose-induced oxidative stress and hypoxia.<\/jats:p>","DOI":"10.3390\/ijms21228577","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T10:32:47Z","timestamp":1605263567000},"page":"8577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia"],"prefix":"10.3390","volume":"21","author":[{"given":"Min-Kyung","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Food science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Il","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Food science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Yeon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Food science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woojin","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Food science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2039-7968","authenticated-orcid":false,"given":"Young-Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/sj.ki.5002222","article-title":"The spectrum of podocytopathies: A unifying view of glomerular diseases","volume":"71","author":"Wiggins","year":"2007","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"412","DOI":"10.3109\/00313028509105494","article-title":"Glomerular podocytic injury in protein overload proteinuria","volume":"17","author":"Davies","year":"1985","journal-title":"Pathology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1152\/physrev.00020.2002","article-title":"Cell biology of the glomerular podocyte","volume":"83","author":"Pavenstadt","year":"2003","journal-title":"Physiol. 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