{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:10:35Z","timestamp":1785186635052,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["grant agreement No 115974"],"award-info":[{"award-number":["grant agreement No 115974"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA\/2J mice were treated with NSC697923 and\/or ramipril. K63-Ub protein accumulation along with \u03b1-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-\u03b1 Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, \u03b1-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.<\/jats:p>","DOI":"10.3390\/ijms22105194","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T10:54:22Z","timestamp":1620989662000},"page":"5194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA\/2J Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-8318","authenticated-orcid":false,"given":"Paola","family":"Pontrelli","sequence":"first","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2863-864X","authenticated-orcid":false,"given":"Francesca","family":"Conserva","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Menghini","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Rossini","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3652-3623","authenticated-orcid":false,"given":"Alessandra","family":"Stasi","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Divella","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3554-0181","authenticated-orcid":false,"given":"Viviana","family":"Casagrande","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cinefra","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariagrazia","family":"Barozzino","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Simone","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Pesce","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Castellano","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Stallone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-9584","authenticated-orcid":false,"given":"Anna","family":"Gallone","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-2678","authenticated-orcid":false,"given":"Francesco","family":"Giorgino","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Federici","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loreto","family":"Gesualdo","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"A6","DOI":"10.1053\/j.ajkd.2019.09.003","article-title":"US Renal Data System 2019 Annual Data Report: Epidemiology of Kidney Disease in the United States","volume":"75","author":"Saran","year":"2020","journal-title":"Am. 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