Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
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.
Kang
Duk-Hee
DH
Division of Nephrology, Ewha Women's University College of Medicine, Seoul, Korea.
Han
Lin
L
Ouyang
Xiaosen
X
Kahn
Andrew M
AM
Kanellis
John
J
Li
Ping
P
Feng
Lili
L
Nakagawa
Takahiko
T
Watanabe
Susumu
S
Hosoyamada
Makoto
M
Endou
Hitoshi
H
Lipkowitz
Michael
M
Abramson
Ruth
R
Mu
Wei
W
Johnson
Richard J
RJ
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*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D027361:Organic Anion Transporters; C103862:urate transporter; D014527:Uric Acid; D011339:Probenecid