{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T05:56:33Z","timestamp":1774677393954,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"medical research grants from the Chang Gung Memorial Hospital at Chiayi, Taiwan","award":["CMRPG6K0231-3"],"award-info":[{"award-number":["CMRPG6K0231-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic kidney disease (DKD) can cause inflammation and fibrosis, in addition to being the main complication of diabetes. Among many factors, epigenetic alterations in aberrant histone modifications play a key role in causing DKD. In this study, the mechanism of GSK-J4, a histone demethylase KDM6A inhibitor, was evaluated in streptozotocin-induced diabetic mice. It was confirmed that GSK-J4, via dickkopf-1 (DKK1) modulation, could significantly reduce proteinuria and glomerulosclerosis in diabetic mice. The mRNA accumulation levels of DKK1, TGF-\u03b21, fibronectin, and collagen IV were significantly elevated in diabetic mice. In contrast, the mRNA accumulations of those genes were significantly reduced in diabetic mice treated with GSK-J4 compared to those in diabetic mice, relatively speaking. The protein accumulation levels of fibronectin and collagen IV were significantly elevated in diabetic mice. Furthermore, GSK-J4 attenuated the high glucose-induced expression of profibrotic factors in mesangial cells via DKK1. In conclusion, our study provides a novel strategy to eliminate fibrosis in the kidneys of DKD mice. Using GSK-J4 reduces DKK1 expression, thereby ameliorating renal insufficiency, glomerulosclerosis morphological abnormalities, inflammation, and fibrosis in diabetic mice.<\/jats:p>","DOI":"10.3390\/ijms23169407","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T22:23:13Z","timestamp":1661120593000},"page":"9407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5963-6981","authenticated-orcid":false,"given":"Peir-Haur","family":"Hung","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan"},{"name":"Department of Applied Life Science and Health, Chia-Nan University of Pharmacy and Science, Tainan 717301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Chien","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-1495","authenticated-orcid":false,"given":"Tsung-Hsien","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-8405","authenticated-orcid":false,"given":"Chun-Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan"},{"name":"Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan"},{"name":"Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833253, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hung, P.H., Hsu, Y.C., Chen, T.H., and Lin, C.L. 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