title: Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts.
abstract: 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)-treated 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-β (TGF-β). 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-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II-induced 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.
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. yangshen13@fudan.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 13111010002@fudan.edu.cn.
authors.forename: Naijun
authors.initials: N
authors.lastname: Miao
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 13211010003@fudan.edu.cn.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 14211010001@fudan.edu.cn.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Gan
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. 14211010003@fudan.edu.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. lizhou@shmu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. xuehong@fudan.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. wzhang@shmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. lulimin@shmu.edu.cn.
authors.forename: Limin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D008687:Metformin
keywords: ERK; angiotensin II; metformin; renal fibrosis; transforming growth factor-β