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Published ahead of print on October 26, 2005
J Am Soc Nephrol 16: 3553-3562, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2005050572
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Hemodynamics and Vascular Regulation

Uric Acid–Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells

Duk-Hee Kang*, Sung-Kwang Park{dagger}, In-Kyu Lee{ddagger} and Richard J. Johnson§

* Division of Nephrology, Ewha Woman’s University College of Medicine, Seoul, Korea; {dagger} Department of Internal Medicine, Chonbuk National University Medical School, Chonju, Korea; {ddagger} Department of Internal Medicine, Kyungpook National University, School of Medicine, Taegu, Korea; and § Division of Nephrology, University of Florida, Gainesville, Florida

Address correspondence to: Dr. Duk-Hee Kang, Division of Nephrology, Ewha Women’s University Hospital, 70 Chongno 6-ka Chongno-ku Seoul 110-126, Korea. Phone: 82-2-760-5121; Fax: 82-2-760-5008; E-mail: dhkang{at}ewha.ac.kr

Received for publication May 31, 2005. Accepted for publication September 7, 2005.

Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal–regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.




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