Document Detail

Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
MedLine Citation:
PMID:  16113518     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Soluble uric acid stimulates vascular smooth muscle cell (VSMC) proliferation by activating mitogen-activated protein kinases, and stimulating COX-2 and PDGF synthesis. The mechanism by which uric acid enters the VSMC is not known. We hypothesized that uric acid enters via transporters similar to that observed in the kidney. METHODS: We studied the uptake of uric acid into rat VSMC under polarized and depolarized conditions and in the presence of organic anion transport (OAT) inhibitors (probenecid and benzbromarone) or p-aminohippurate (PAH). We also examined the ability of probenecid to inhibit uric acid-induced VSMC proliferation and monocyte chemoattractant protein-1 (MCP-1) synthesis. RESULTS: (14)C-Urate uptake was shown in VSMC and was enhanced under depolarized conditions. (14)C-Uric acid uptake was inhibited by probenecid and benzbromarone, as well as by unlabelled urate and PAH. Probenecid blocked VSMC proliferation and MCP-1 expression in response to uric acid. VSMC did not express rOAT1-3, rOAT-5 or URAT-1 mRNA by PCR, but did express the voltage-sensitive transporter (UAT) by both PCR and RNase protection assay. CONCLUSIONS: Urate enters VSMC by both voltage-sensitive and OAT pathways, and the uptake, cell proliferation and MCP-1 expression can be blocked by OAT inhibitors. The specific transporter(s) responsible for the urate uptake remains to be determined.
Duk-Hee Kang; Lin Han; Xiaosen Ouyang; Andrew M Kahn; John Kanellis; Ping Li; Lili Feng; Takahiko Nakagawa; Susumu Watanabe; Makoto Hosoyamada; Hitoshi Endou; Michael Lipkowitz; Ruth Abramson; Wei Mu; Richard J Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-08-19
Journal Detail:
Title:  American journal of nephrology     Volume:  25     ISSN:  0250-8095     ISO Abbreviation:  Am. J. Nephrol.     Publication Date:    2005 Sep-Oct
Date Detail:
Created Date:  2005-10-10     Completed Date:  2005-12-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8109361     Medline TA:  Am J Nephrol     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  425-33     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2005 S. Karger AG, Basel.
Division of Nephrology, Ewha Women's University College of Medicine, Seoul, Korea.
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MeSH Terms
Cell Proliferation / drug effects
Cells, Cultured
Chemokine CCL2 / antagonists & inhibitors,  biosynthesis
Muscle, Smooth, Vascular / cytology*,  metabolism*
Myocytes, Smooth Muscle / cytology*,  metabolism
Organic Anion Transporters / antagonists & inhibitors,  metabolism*
Probenecid / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Uric Acid / pharmacokinetics*,  pharmacology*
Grant Support
1P50 DK 064233-01/DK/NIDDK NIH HHS; R01 HL 68607/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Ccl2 protein, rat; 0/Chemokine CCL2; 0/Organic Anion Transporters; 0/urate transporter; 57-66-9/Probenecid; 69-93-2/Uric Acid

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