Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter

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

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

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: 14C-Urate uptake was shown in VSMC and was enhanced under depolarized conditions. 14C-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.

Original languageEnglish
Pages (from-to)425-433
Number of pages9
JournalAmerican Journal of Nephrology
Volume25
Issue number5
DOIs
StatePublished - Sep 2005

Keywords

  • Hypertension
  • Uric acid
  • Uricosuric agent
  • Vascular smooth muscle cell

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