{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T05:53:04Z","timestamp":1793857984465,"version":"4.6.1"},"reference-count":28,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T00:00:00Z","timestamp":1453420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81470591"],"award-info":[{"award-number":["81470591"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81170636"],"award-info":[{"award-number":["81170636"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81100531"],"award-info":[{"award-number":["81100531"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)\u2013treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-\u03b2 (TGF-\u03b2). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-\u03b2 in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II\u2013induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms17020146","type":"journal-article","created":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T11:36:13Z","timestamp":1453462573000},"page":"146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts"],"prefix":"10.3390","volume":"17","author":[{"given":"Yang","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naijun","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1172\/JCI72267","article-title":"Cellular and molecular mechanisms in kidney fibrosis","volume":"124","author":"Duffield","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/nrneph.2011.149","article-title":"Cellular and molecular mechanisms of renal fibrosis","volume":"7","author":"Liu","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nrneph.2012.280","article-title":"Chronic kidney disease following acute kidney injury-risk and outcomes","volume":"9","author":"Leung","year":"2013","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"C591","DOI":"10.1152\/ajpcell.00414.2012","article-title":"Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis","volume":"304","author":"Campanholle","year":"2013","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/kisup.2014.2","article-title":"Overview of the cellular and molecular basis of kidney fibrosis","volume":"4","author":"Eddy","year":"2014","journal-title":"Kidney Int. Suppl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/ki.2014.287","article-title":"Origin of myofibroblasts and cellular events triggering fibrosis","volume":"87","author":"Mack","year":"2015","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1093\/ndt\/gfs296","article-title":"The renal (myo-)fibroblast: A heterogeneous group of cells","volume":"27","author":"Boor","year":"2012","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"F986","DOI":"10.1152\/ajprenal.00595.2011","article-title":"Smad3 mediates ANG II-induced hypertensive kidney disease in mice","volume":"302","author":"Liu","year":"2012","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1038\/sj.ki.5001846","article-title":"Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-\u03b2 pathway","volume":"70","author":"Wolf","year":"2006","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1681\/ASN.2010040384","article-title":"Angiotensin II as a morphogenic cytokine stimulating renal fibrogenesis","volume":"22","author":"Ruster","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/kisup.2014.11","article-title":"Key fibrogenic mediators: Old players. Renin-angiotensin system","volume":"4","author":"Macconi","year":"2014","journal-title":"Kidney Int. Suppl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev-med-062613-093128","article-title":"Metformin in cancer treatment and prevention","volume":"66","author":"Morales","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/j.1478-3231.2010.02223.x","article-title":"Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease","volume":"30","author":"Donadon","year":"2010","journal-title":"Liver Int."},{"key":"ref_15","first-page":"59","article-title":"Metformin may function as anti-cancer agent via targeting cancer stem cells: The potential biological significance of tumor-associated miRNAs in breast and pancreatic cancers","volume":"2","author":"Bao","year":"2014","journal-title":"Ann. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kita, Y., Takamura, T., Misu, H., Ota, T., Kurita, S., Takeshita, Y., Uno, M., Matsuzawa-Nagata, N., Kato, K., and Ando, H. (2012). Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043056"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"877","DOI":"10.3892\/ijmm.2015.2092","article-title":"MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis","volume":"35","author":"Katsura","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.mce.2015.06.006","article-title":"Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction","volume":"412","author":"Cavaglieri","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s11255-013-0520-1","article-title":"Unilateral ureteral obstruction: Beyond obstruction","volume":"46","author":"Ucero","year":"2014","journal-title":"Int. Urol. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/ki.2009.86","article-title":"Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy","volume":"75","author":"Chevalier","year":"2009","journal-title":"Kidney Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nrneph.2014.31","article-title":"Novel targets of antifibrotic and anti-inflammatory treatment in CKD","volume":"10","author":"Decleves","year":"2014","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/bph.12159","article-title":"ACE2, angiotensin-(1\u20137) and Mas receptor axis in inflammation and fibrosis","volume":"169","author":"Simoes","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/HYPERTENSIONAHA.109.136531","article-title":"Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-\u03b2-dependent and -independent Smad pathways: The role of Smad3","volume":"54","author":"Yang","year":"2009","journal-title":"Hypertension"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1111\/j.1523-1755.2004.00901.x","article-title":"Combining TGF-\u03b2 inhibition and angiotensin II blockade results in enhanced antifibrotic effect","volume":"66","author":"Yu","year":"2004","journal-title":"Kidney Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/labinvest.2012.2","article-title":"Loss of angiotensin-converting enzyme 2 enhances TGF-\u03b2\/Smad-mediated renal fibrosis and NF-\u03baB-driven renal inflammation in a mouse model of obstructive nephropathy","volume":"92","author":"Liu","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"H69","DOI":"10.1152\/ajpheart.00341.2008","article-title":"Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1\/2 MAP kinase, \u03b1v\u03b23-integrin, and TGF-\u03b21 in response to ANG II and high glucose","volume":"295","author":"Belmadani","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/jcb.20380","article-title":"Advanced glycation end-product-induced mitogenesis and collagen production are dependent on angiotensin II and connective tissue growth factor in NRK-49F cells","volume":"95","author":"Lee","year":"2005","journal-title":"J. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1128\/MCB.06410-11","article-title":"Angiotensin II induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species\/Src\/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway","volume":"32","author":"Chen","year":"2012","journal-title":"Mol. Cell. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/2\/146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:18:11Z","timestamp":1760210291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/2\/146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,22]]},"references-count":28,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2016,2]]}},"alternative-id":["ijms17020146"],"URL":"https:\/\/doi.org\/10.3390\/ijms17020146","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,22]]}}}