title: COX-2/mPGES-1/PGE2 cascade activation mediates uric acid-induced mesangial cell proliferation.
abstract: Hyperuricemia is not only the main feature of gout but also a cause of gout-related organ injuries including glomerular hypertrophy and sclerosis. Uric acid (UA) has been proven to directly cause mesangial cell (MC) proliferation with elusive mechanisms. The present study was undertaken to examined the role of inflammatory cascade of COX-2/mPGES-1/PGE2 in UA-induced MC proliferation. In the dose- and time-dependent experiments, UA increased cell proliferation shown by the increased total cell number, DNA synthesis rate, and the number of cells in S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. Interestingly, UA-induced cell proliferation was accompanied with the upregulation of COX-2 and mPGES-1 at both mRNA and protein levels. Strikingly, inhibition of COX-2 via a specific COX-2 inhibitor NS-398 markedly blocked UA-induced MC proliferation. Meanwhile, UA-induced PGE2 production was almost entirely abolished. Furthermore, inhibiting mPGES-1 by a siRNA approach in MCs also ameliorated UA-induced MC proliferation in line with a significant blockade of PGE2 secretion. More importantly, in gout patients, we observed a significant elevation of urinary PGE2 excretion compared with healthy controls, indicating a translational potential of this study to the clinic. In conclusion, our findings indicated that COX-2/mPGES-1/PGE2 cascade activation mediated UA-induced MC proliferation. This study offered new insights into the understanding and the intervention of UA-related glomerular injury.
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Jiangsu Province Hospital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing 210008, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 210029, USA.
authors.forename: John Ci-Jiang
authors.initials: JC
authors.lastname: He
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.|Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D056751:Cyclin A2 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006073:Gout / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000652:urine; D006801:Humans; D033461:Hyperuricemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000652:urine; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: C508184:CCNA2 protein, mouse; C530105:Ccnd1 protein, mouse; D056751:Cyclin A2; D052246:Cyclooxygenase 2 Inhibitors; D019938:Cyclin D1; D014527:Uric Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: COX-2; PGE2; mPGES-1; mesangial cells; uric acid