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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068607-05
Application #
6851721
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Barouch, Winifred
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$375,156
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Lanaspa, Miguel A; Epperson, L Elaine; Li, Nanxing et al. (2015) Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One 10:e0123509
Rodríguez-Iturbe, Bernardo; Pons, Héctor; Quiroz, Yasmir et al. (2014) Autoimmunity in the pathogenesis of hypertension. Nat Rev Nephrol 10:56-62
Cicerchi, Christina; Li, Nanxing; Kratzer, James et al. (2014) Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J 28:3339-50
Lanaspa, Miguel A; Ishimoto, Takuji; Cicerchi, Christina et al. (2014) Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 25:2526-38
Rodríguez-Iturbe, Bernardo; Pons, Héctor; Quiroz, Yasmir et al. (2014) The immunological basis of hypertension. Am J Hypertens 27:1327-37
Chen, Wei; Roncal-Jimenez, Carlos; Lanaspa, Miguel et al. (2014) Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo. Metabolism 63:150-60
Franco, Martha; Tapia, Edilia; Bautista, Rocio et al. (2013) Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. Am J Physiol Renal Physiol 304:F982-90
Johnson, Richard J; Rivard, Chris; Lanaspa, Miguel A et al. (2013) Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection? Journal of equine veterinary science 33:120-126
Pons, Hector; Ferrebuz, Atilio; Quiroz, Yasmir et al. (2013) Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension. Am J Physiol Renal Physiol 304:F289-99
Rodriguez-Iturbe, Bernardo; Franco, Martha; Johnson, Richard J (2013) Impaired pressure natriuresis is associated with interstitial inflammation in salt-sensitive hypertension. Curr Opin Nephrol Hypertens 22:37-44

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