The presence of an elevated serum uric acid is strongly associated with hypertension and renal disease. Despite the association and the ease with which to treat this condition, it remains unknown if the elevated uric acid has a pathogenic role in cardiovascular disease or whether it simply represents a 'marker' for other associated risk factors. Epidemiological studies have been unable to resolve this issue, and experimental studies have been thwarted by the absence of an animal model of mild hyperuricemia and by a paucity of cell culture studies. In preliminary data we have developed a model of mild hyperuricemia in rats and have found that they develop hypertension after several weeks through a crystal independent mechanism in which an afferent arteriolopathy develops in association with alterations in the renin angiotensin, cyclooxygenase-2 and nitric oxide pathways in the kidney. Mild hyperuricemia also results in interstitial renal disease, and hyperuricemia exacerbates renal injury in two different animal models. Our central hypothesis is that hyperuricemia induces hypertension and renal disease acutely by stimulating COX-2 in vascular smooth muscle cells and in the macula densa, which subsequently stimulates renin production, inhibits macula densa nitric oxide synthase, and raises blood pressure. Hyperuricemia also causes a primary afferent arteriolopathy that we hypothesize is mediated by local PDGF expression, and we postulate that once the arteriolopathy is established that salt-sensitive hypertension will persist even if the uric acid levels are corrected.
In aim 1 we will examine the role of COX2 in our model, and will examine the kinetics of its expression and the effect of inhibition of COX2 on the alterations in renin, nitric oxide synthase, blood pressure and renal lesions.
In aim 2 we will study the mechanism by which uric acid induces the arteriolopathy in our rats, and we will concentrate on the role of PDGF; furthermore, we will determine if the arteriolopathy provides a mechanism by which hypertension will be self-sustained despite correction of the hyperuricemia.
In aim 3 we will initiate studies of the cellular mechanism by which uric acid stimulates PDGF and COX2 in cultured vascular smooth muscle cells and macula densa cells, with emphasis on the role of the recently cloned urate channel and on the MAP kinase cascade. Given that there are over 20 million individuals with hyperuricemia in the United States, and that 25-50% of all hypertensive individuals are hyperuricemic, we believe that studies examining the role of hyperuricemia in hypertension and cardiovascular disease are strongly indicated. We believe that the preliminary data, coupled with the studies proposed, provide the first insights into a potential pathogenic mechanism by which uric acid induces hypertension and renal disease in rats, and may well provide important insights into the role of hyperuricemia in hypertension, cardiovascular and renal disease in man.
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