Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.
BACKGROUND
Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however.


METHODS
We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS). Rat VSMC were exposed to 0-300 micromol uric acid for 48 h.


RESULTS
Uric acid (200 and 300 micromol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10(-6) mol losartan or by 10(-6) mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril.


CONCLUSIONS
These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.
Corry
Dalila B
DB
Olive View UCLA Medical Center, Sylmar, USA.
Eslami
Pirooz
P
Yamamoto
Kei
K
Nyby
Michael D
MD
Makino
Hirofumi
H
Tuck
Michael L
ML
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000254:growth & development; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032342:Muscle Cells / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*; D014527:Uric Acid / Q000378:metabolism*
D000804:Angiotensin II; D014527:Uric Acid; D020929:Mitogen-Activated Protein Kinase Kinases