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Am J Physiol Renal Physiol. 2014 Aug 15;307(4):F396-406. doi: 10.1152/ajprenal.00565.2013. Epub 2014 Feb 26.

Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation.

Author information

1
Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
2
Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and.
3
Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
4
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.

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.

KEYWORDS:

ERK1/2; cell proliferation; mesangial cells; reactive oxygen species; uric acid

PMID:
24573389
DOI:
10.1152/ajprenal.00565.2013
[Indexed for MEDLINE]
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