title: Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation.
abstract: Hyperuricemia is associated with kidney complications including glomerulosclerosis and mesangial cell (MC) proliferation by poorly understood mechanisms. The present study investigated the underlying mechanisms that mediate uric acid (UA)-induced MC proliferation. A rat MC line, HBZY-1, was treated with various concentrations of UA in the presence or absence of a specific extracellular-regulated protein kinase 1/2 (ERK1/2) inhibitor (U0126), apocynin. UA dose dependently stimulated MC proliferation as shown by increased DNA synthesis and number of cells in the S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. In addition, UA time dependently promoted MC proliferation and significantly increased phosphorylation of ERK1/2 but not c-Jun NH2-terminal kinase and p38 MAPK in MCs as assessed by immunoblotting. Inhibition of ERK1/2 signaling via U0126 markedly blocked UA-induced MC proliferation. More importantly, UA induced intracellular reactive oxygen species (ROS) production of MCs dose dependently, which was completely blocked by apocynin, a specific NADPH oxidase inhibitor. Toll-like receptor (TLR)2 and TLR4 signaling had no effect on NADPH-derived ROS and UA-induced MC proliferation. Interestingly, pretreatment with apocynin inhibited ERK1/2 activation, the upregulation of cyclin A2 and cyclin D1, and MC proliferation. In conclusion, UA-induced MC proliferation was mediated by NADPH/ROS/ERK1/2 signaling pathway. This novel finding not only reveals the mechanism of UA-induced MC cell proliferation but also provides some potential targets for future treatment of UA-related glomerular injury.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Quancheng
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Ruochen
authors.initials: R
authors.lastname: Che
authors.affiliation: Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Huaying
authors.initials: H
authors.lastname: Bao
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China smhuang@njmu.edu.cn.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D056751:Cyclin A2 / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D005419:Flavonoids / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D002070:Butadienes; C503722:Ccna2 protein, rat; C530106:Ccnd1 protein, rat; D056751:Cyclin A2; D005419:Flavonoids; D009570:Nitriles; D017382:Reactive Oxygen Species; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C113580:U 0126; D019938:Cyclin D1; D014527:Uric Acid; C056165:acetovanillone; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ERK1/2; cell proliferation; mesangial cells; reactive oxygen species; uric acid