Hyperuricemia induces endothelial dysfunction

Uday M. Khosla, Sergey Zharikov, Jennifer L. Finch, Takahiko Nakagawa, Carlos Roncal, Wei Mu, Karina Krotova, Edward R. Block, Sharma Prabhakar, Richard J. Johnson

Research output: Contribution to journalArticlepeer-review

783 Scopus citations

Abstract

Background. Hyperuricemia has been linked to cardiovascular and renal diseases, possibly through the generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction. The enzymatic effect of xanthine oxidase is the production of ROS and uric acid. Studies have shown that inhibiting xanthine oxidase with allopurinol can reverse endothelial dysfunction. Furthermore, rat studies have shown that hyperuricemia-induced hypertension and vascular disease is at least partially reversed by the supplementation of the nitric oxide synthase (NOS) substrate, L-arginine. Therefore, we hypothesized that uric acid induces endothelial dysfunction by inhibiting nitric oxide production. Methods. Hyperuricemia was induced in male Sprague-Dawley rats with an uricase inhibitor, oxonic acid, by gavage; control rats received vehicle. Allopurinol was placed in drinking water to block hyperuricemia. Rats were randomly divided into four groups: (1) control, (2) allopurinol only, (3) oxonic acid only, and (4) oxonic acid + allopurinol. Rats were sacrificed at 1 and 7 days, and their serum analyzed for serum uric acid and nitrites/nitrates concentrations. The effect of uric acid on nitric oxide production was also determined in bovine aortic endothelial cells. Results. Oxonic acid induced mild hyperuricemia at both 1 and 7 days (P < 0.05). Allopurinol reversed the hyperuricemia at 7 days (P <. 001). Serum nitrites and nitrates (NOX) were reduced in hyperuricemic rats at both 1 and 7 days (P < .001). Allopurinol slightly reversed the decrease in NOX at 1 day and completely at 7 days (P < .001). There was a direct linear correlation between serum uric acid and NOX (R2 = 0.56) and a trend toward higher systolic blood pressure in hyperuricemic rats (P = NS). Uric acid was also found to inhibit both basal and vascular endothelial growth factor (VEGF)-induced nitric oxide production in bovine aortic endothelial cells. Conclusion. Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.

Original languageEnglish (US)
Pages (from-to)1739-1742
Number of pages4
JournalKidney international
Volume67
Issue number5
DOIs
StatePublished - May 2005
Externally publishedYes

Keywords

  • Endothelial dysfunction
  • Nitric oxide
  • Uric acid

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