COX-2/mPGES-1/PGE2 cascade activation mediates uric acid-induced mesangial cell proliferation
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Shuzhen Li1,2,3,*, Zhenzhen Sun1,2,3,*, Yue Zhang1,2,3, Yuan Ruan4, Qiuxia Chen1,2,3, Wei Gong1,2,3, Jing Yu1,2,3, Weiwei Xia1,2,3, John Ci-Jiang He5, Songming Huang1,2,3, Aihua Zhang1,2,3, Guixia Ding1,2,3, Zhanjun Jia1,2,3
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
4Department of Endocrinology, Jiangsu Province Hospital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing 210008, China
5Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 210029, USA
*These authors have contributed equally to this work
Zhanjun Jia, email: email@example.com
Guixia Ding, email: firstname.lastname@example.org
Keywords: uric acid, COX-2, mPGES-1, PGE2, mesangial cells
Received: October 11, 2016 Accepted: December 13, 2016 Published: December 29, 2016
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.
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