{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:45:59Z","timestamp":1781743559740,"version":"3.54.5"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,5]],"date-time":"2020-01-05T00:00:00Z","timestamp":1578182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004606","name":"Chang Gung Medical Foundation","doi-asserted-by":"publisher","award":["CMRPG6F0501"],"award-info":[{"award-number":["CMRPG6F0501"]}],"id":[{"id":"10.13039\/501100004606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["106-2314-B-182A-101"],"award-info":[{"award-number":["106-2314-B-182A-101"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tubulointerstitial fibrosis is a major pathological hallmark of diabetic nephropathy. Increasing evidence has shown that epithelial-to-mesenchymal transition (EMT) of renal proximal tubular cells plays a crucial role in tubulointerstitial fibrosis. Herein, we aimed to elucidate the detailed mechanism of EMT in renal tubular cells under high glucose (HG) conditions, and to investigate the potential of licorice, a medicinal herb, to inhibit HG-induced EMT. Our results showed that renal tubular epithelial cells (normal rat kidney cell clone 52E; NRK-52E) exposed to HG resulted in EMT induction characterized by increased fibronectin and \u03b1-SMA (alpha-smooth muscle actin) but decreased E-cadherin. Elevated levels of cleaved Notch2, MAML-1 (mastermind-like transcriptional coactivator 1), nicastrin, Jagged-1 and Delta-like 1 were also concomitantly detected in HG-cultured cells. Importantly, pharmacological inhibition, small interfering RNA (siRNA)-mediated depletion or overexpression of the key components of Notch2 signaling in NRK-52E cells supported that the activated Notch2 pathway is essential for tubular EMT. Moreover, we found that licorice extract (LE) with or without glycyrrhizin, one of bioactive components in licorice, effectively blocked HG-triggered EMT in NRK-52E cells, mainly through suppressing the Notch2 pathway. Our findings therefore suggest that Notch2-mediated renal tubular EMT could be a therapeutic target in diabetic nephropathy, and both LE and de-glycyrrhizinated LE could have therapeutic potential to attenuate renal tubular EMT and fibrosis.<\/jats:p>","DOI":"10.3390\/cells9010125","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T03:48:48Z","timestamp":1578282528000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["De-Glycyrrhizinated Licorice Extract Attenuates High Glucose-Stimulated Renal Tubular Epithelial\u2013Mesenchymal Transition via Suppressing the Notch2 Signaling Pathway"],"prefix":"10.3390","volume":"9","author":[{"given":"Yung-Chien","family":"Hsu","sequence":"first","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-0346","authenticated-orcid":false,"given":"Pey-Jium","family":"Chang","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Wu","family":"Tung","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Hsueh","family":"Shih","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chiu","family":"Ni","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chen","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuhiro","family":"Uto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Shoyama","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-8405","authenticated-orcid":false,"given":"Chun-Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan"},{"name":"Kidney Research Center, Chang Gung Memorial Hospital, Taipei 105, Taiwan"},{"name":"School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1053\/j.ajkd.2013.10.047","article-title":"New insights into molecular mechanisms of diabetic kidney disease","volume":"63","author":"Badal","year":"2014","journal-title":"Am. 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