title: Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
abstract: 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.
authors.affiliation: Division of Nephrology, Ewha Women's University College of Medicine, Seoul, Korea.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
authors.forename: Lin
authors.initials: L
authors.lastname: Han
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kahn
authors.forename: John
authors.initials: J
authors.lastname: Kanellis
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Watanabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Hosoyamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Michael
authors.initials: M
authors.lastname: Lipkowitz
authors.forename: Ruth
authors.initials: R
authors.lastname: Abramson
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014527:Uric Acid / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D027361:Organic Anion Transporters; C103862:urate transporter; D014527:Uric Acid; D011339:Probenecid