Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism

An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these comp lications remains controversial. We tested the hypothesis that uric acid ma y have a causal role in the development of hypertension and renal disease b y examining the effects of mild hyperuricemia in rats. Mild hyperuricemia w as induced in rats by providing a uricase inhibitor (oxonic acid) in the di et. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whe reas control rats remained normotensive. The development of hypertension wa s prevented by concurrent treatment with either a xanthine oxidase inhibito r (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric ac id levels with either allopurinol or oxonic acid withdrawal. A direct relat ionship was found between blood pressure and uric acid (r=0.75, n=69). with a 10-mm He, blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incre mental rise in serum uric acid. The kidneys were devoid of urate crystals a nd were normal by light microscopy. However, immunohistochemical stains doc umented an ischemic type of injury with collagen deposition, macrophage inf iltration, and an increase in tubular expression of osteopontin. Hyperurice mic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertensi on were reduced by treatment with enalapril or L-arginine. In conclusion, m ild hyperuricemia causes hypertension and renal injury in the rat via a cry stal-independent mechanism, with stimulation of the renin-angiotensin syste m and inhibition of neuronal NO synthase.