Uric Acid and the State of the Intrarenal Renin-Angiotensin System in Humans

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Kidney International, Vol. 66 (2004), pp. 1465–1470

VASCULAR BIOLOGY – HEMODYNAMICS – HYPERTENSION

Uric acid and the state of the intrarenal renin-angiotensin system in humans

TODD S. PERLSTEIN,OLGA GUMIENIAK,PAUL N. HOPKINS,LAINE J. MURPHEY,NANCY J. BROWN, GORDON H. WILLIAMS,NORMAN K. HOLLENBERG, and NAOMI D.L. FISHER

Endocrinology, Diabetes and Hypertension Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Cardiovascular Genetics, University of Utah, Salt Lake City, Utah; and the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

Uric acid and the state of the intrarenal renin-angiotensin sys- Controversy exists regarding the relationship of uric tem in humans. acid to hypertension and renal disease in humans [1, 2]. Background. Experimental hyperuricemia is marked by an It is unclear whether an elevation in uric acid concen- activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides tration contributes to or simply reflects disturbed renal an indirect measure of intrarenal RAS activity. We tested the physiology such as alterations in the renal vasculature [3] hypothesis that the serum uric acid concentration predicts the or in the tubular handling of sodium [4]. Recent work in renal vascular response to Ang II. experimental hyperuricemia suggests that uric acid might Methods. A total of 249 subjects in high sodium balance had have a pathogenetic role in hypertension and nephropa- the renal plasma flow (RPF) response to Ang II measured. Para- aminohippuric acid (PAH) clearance was used to estimate RPF. thy. The hyperuricemic rat develops hypertension [5], Multivariable regression analysis determined if the serum uric and the kidney of the hyperuricemic rat develops affer- acid concentration independently predicts the RPF response ent arteriolopathy [6], glomerular hypertrophy [7], and to Ang II. Variables considered included age, gender, race, interstitial inflammation [5]. Renal renin expression is body mass index (BMI), hypertension status, blood pressure, increased, and angiotensin-converting enzyme (ACE) in- basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and hibition ameliorates the kidney damage [6]. These ob- plasma renin activity (PRA). servations raise the possibility of a uric acid–induced Results. Uric acid concentration negatively correlated with nephropathy, and implicate activation of the intrarenal the RPF response to Ang II (r = −0.37, P < 0.001). In univari- renin-angiotensin system (RAS) as a mediator of uric ate analysis, age, BMI, hypertension, triglycerides, and blood acid–induced nephropathy. pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response At the present time, there is no readily available means to Ang II. In multivariable analysis, serum uric acid concentra- of directly assessing intrarenal RAS activity in humans. tion independently predicted the RPF response to Ang II (b = We have employed the renal vascular response to infused −5.3, P < 0.001). angiotensin II (Ang II) as an indirect measure of activity Conclusion. Serum uric acid independently predicted of the intrarenal vascular RAS [8]. Multiple lines of ev- blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated idence indicate that the response is inversely correlated intrarenal RAS. This could be due to a direct effect of uric acid with endogenous RAS activity [9–12]. In light of the ani- or reflect a more fundamental renal process. These data may mal data suggesting that uric acid activates the intrarenal have relevance to the association of uric acid with risk for hy- RAS, we examined whether the serum uric acid concen- pertension and nephropathy. tration predicts the renal vascular response to Ang II in humans.

METHODS

Keywords: uric acid, kidney, angiotensin, vascular. Subjects and protocol Subjects in this report were studied by the international Received for publication January 13, 2004 and in revised form April 14, 2004 HyperPath (Hypertensive Pathotype) group. Included in Accepted for publication April 28, 2004 this report are a total 249 Caucasian and African Amer- ican subjects who completed renal plasma ﬂow (RPF) C 2004 by the International Society of Nephrology studies in high salt balance and had the serum uric acid

1465 1466 Perlstein et al: Uric acid and the intrarenal RAS in humans

Table 1. Characteristics of subjects All subjects Normotensives Hypertensives P valuea Number 249 80 169 Age years 45.0 ± 10 37.7 ± 11 48.4 ± 7.4 <0.001 Gender female % 45 60 38 0.001 Race black % 11 18 9 0.05 Hypertension status HTN % 68 NA NA NA Body mass index kg/m2 28.0 ± 4.4 25.9 ± 5.1 28.9 ± 3.7 <0.001 Systolic blood pressure mm Hg 132 + 23 110 + 13 142 + 19 <0.001 Diastolic blood pressure mm Hg 79.6 ± 13 66.4 ± 8.6 85.4 ± 10 <0.001 Fasting serum glucose mg/dL 87.7 ± 22 86.4 ± 25 88.2 ± 21 0.57 Fasting serum insulin uU/mL 11.3 ± 8.5 10.6 ± 6.3 11.7 ± 9.3 0.27 Serum total cholesterol mg/dL 184 ± 34 168 ± 32 191 ± 33 <0.001 Serum triglycerides mg/dL 162 ± 89 124 ± 84 176 ± 87 <0.001 Serum HDL mg/dL 42 ± 12 45 ± 13 41 ± 11 0.05 Serum uric acid mg/dL 5.4 ± 1.6 4.6 ± 1.6 5.8 ± 1.5 <0.001 PRA ng Ang I/mL/sec 0.49 ± 0.50 0.47 ± 0.43 0.49 ± 0.55 0.78 Creatinine clearance mL/min 107 ± 34 108 ± 30 107 ± 36 0.79 24 hour urine sodium mmol 240 ± 64 235 ± 65 243 ± 64 0.36 Basal RPF mL/min/1.73 m2 530 ± 109 591 ± 100 501 ± 102 <0.001

Abbreviations are: RPF, renal plasma flow; HTN, hypertension; PRA, plasma renin activity; HDL, high density lipoprotein. aP values for hypertensives vs. normotensives. Continuous values reported as mean ± SD, discrete as percentile. concentration measured. We performed this analysis on having a blood pressure <140/90 mm Hg, normotensives subjects studied during high sodium balance because of did not have a first-degree relative with hypertension on- the greater range of responsiveness during high sodium set before 60 years of age. All subjects had a screening balance [10] allows for easier detection of interindivid- history and physical and laboratory examination. Exclu- ual differences. Subjects were studied at the General sion criteria included diabetes mellitus, renal insufficiency Clinical Research Centers (GCRCs) of the Brigham and (serum creatinine >1.5 mg/dL), secondary forms of Women’s Hospital in Boston (N = 90), the University hypertension (based on history, physical examination, of Utah Medical Center in Salt Lake City (N = 133), multichannel serum chemistry screening, and further or the Vanderbilt University Hospital (N = 26). The In- evaluation when indicated), or any other significant med- stitutional Review Board of each center approved the ical problem. ACE inhibitors and angiotensin receptor study, and all subjects gave written informed consent be- blockers were discontinued 3 months before study; all fore enrollment, as described previously [13]. Protocols other antihypertensive medications were stopped for at were carefully standardized at each site through start-up least 2 weeks. and periodic visits between clinic sites, regular conference All subjects consumed a high salt diet (200 mmol calls, and use of common written protocols and clinical sodium) for 3 to 7 days prior to study. High sodium bal- data collection forms. All assays were performed at a cen- ance was defined by urinary excretion of ≥150 mmol tral laboratory. Renal vascular responsiveness in a subset sodium/24 hours. Subjects were admitted to a metabolic of these subjects has been reported, but the analyses re- ward the night before studies. Effective RPF [as para- lating it to uric acid are novel. aminohippuric acid (PAH) clearance] was calculated Of the 249 subjects, there were 152 with no other sibling from steady-state plasma PAH concentrations as previ- included, 94 from sibling pairs, and 3 from a trio. The clin- ously described [13, 14]. Effective RPF was normalized ical and biologic characteristics of these subjects are in- to a body surface area (BSA) of 1.73 m2 by the equa- dicated in Table 1. The mean age of the subjects was 45 ± tion BSA = W0.452 × H0.0725 × 0.007184, where BSA is 10 years, 45% were female, 11% were black, and 68% in square meters, H is height in centimeters, and W is were hypertensive. The mean serum uric acid concentra- weight in kilograms. Ang II was infused at 3 ng/kg/min tion was 5.4 mg/dL (range 1.7 to 10.0 mg/dL) (normal < for 55 minutes on the study day. The RPF response to 7.8 mg/dL in our laboratory). No study subject was taking Ang II was calculated by subtracting the post-Ang II PAH allopurinol. clearance from the pre-Ang II PAH clearance. Diastolic Hypertension was defined as a diastolic blood pressure blood pressure was determined as the mean of three con- of ≥100 mm Hg off medication, or ≥90 mm Hg while tak- secutive readings (by Dinamap) separated by 5 minutes, ing ≥ one medications, or treatment with ≥ two medica- each measured at bed rest on the morning of the study. tions. Siblings had to have a diastolic blood pressure of Creatinine clearance (mL/min) was calculated as [(urine ≥90 mm Hg off medication on ≥ three occasions or di- creatinine (mg/dL)/serum creatinine (mg/dL)] ∗ [urine astolic blood pressure of ≥80 mm Hg on one antihyper- volume (mL)/time (hour) ∗ 60]. Details of all laboratory tensive medication on ≥ three occasions. In addition to assays have been described previously [13, 14]. Uric acid, Perlstein et al: Uric acid and the intrarenal RAS in humans 1467 drawn at the screening visit, was measured by a com- 160 mercially available assay (Olympus, Melville, NY, USA). 140 P value < 0.001 Serum glucose, serum insulin, lipid profile and plasma 2 120 renin activity (PRA) were measured fasting and supine. 100 80 Statistical analysis 60 Statistical analysis was performed with STATA ver- mL/min/1.73m 40 sion 8.0. Subjects’ characteristics are expressed as means 20 and SD values for continuous variables and percent- RPF response to Ang II, 0 ages for discrete variables. Pearson or Spearman correla- 3.4 mg/dL 4.7 mg/dL 5.9 mg/dL 7.5 mg/dL tions were generated for parametric and nonparametric [1.7; 4.2] [4.3; 5.2] [5.3; 6.4] [6.5; 10.0] variables, respectively, with statistical significance deter- Uric acid quartile mined by univariate regression analysis. All regression analyses were clustered by family to account for non- Fig. 1. The renal plasma flow (RPF) response to angiotensin II (Ang II) decreases with increasing quartile of uric acid. Bars represent mean independence of related subjects. Hierarchical multivari- response per quartile, error bars are ± standard error. Groups compared able linear regression was used to determine if the serum by analysis of variance (ANOVA). Labeled are the mean and range of uric acid level is an independent predictor of the RPF re- serum uric acid concentration for each quartile. sponse to Ang II; forward and backward stepping yielded the same result. All variables not included in the final model were tested for confounding; if a variable changed sure, age, serum triglycerides, and serum insulin were pos- ≥ the effect estimate of uric acid by 20%, it was in- itively correlated while serum HDL correlated negatively cluded in the final model. Variables considered were age, with the serum uric acid concentration. gender, race, hypertension status, systolic and diastolic We analyzed to what extent the variation in serum uric blood pressure, body mass index (BMI), serum glucose, acid concentration could be predicted by baseline char- serum insulin, serum total cholesterol, serum triglyc- acteristics. A regression model including basal RPF and erides, serum high-density lipoprotein (HDL) choles- serum insulin explained 11% of the variation in the serum terol, PRA, creatinine clearance, and 24-hour urinary uric acid. A regression model expanded to include all sodium excretion. Dummy variables were used for gen- characteristics that correlated with the serum uric acid der, race, hypertension status, and site to generate inter- (P value for correlation < 0.10) explained 34% of the action terms. Diagnostic tests of leverage and influence variation serum uric acid concentration. were used to evaluate the validity of the model. To examine possible confounding of including both normotensives and hypertensives in the analysis, we in- vestigated if the relationship between serum uric acid RESULTS concentration and the RPF response to Ang II differed Among all subjects, the mean renal plasma flow re- between normotensives and hypertensives. As seen in sponse to Ang II was 104 ± 50 mL/min/1.73 m2.Figure 1 Table 1, hypertensives were older, more frequently male, demonstrates that the mean RPF response to Ang II heavier, had a higher serum uric acid concentration, decreases significantly by quartile serum uric acid con- higher systolic blood pressure and diastolic blood pres- centration (P < 0.001). In univariate analysis, basal RPF sure, and lower basal RPF. Despite these differences, in was the strongest correlate of this response (r = 0.67, univariate analysis the correlation and slope of the rela- P < 0.001) (Table 2). Age, BMI, systolic blood pressure, tionship between the serum uric acid level and the RPF diastolic blood pressure, and serum triglycerides also response to Ang II were almost identical in normoten- negatively correlated with the RPF response to Ang II. sives (r = −0.26, b = −8.2, P = 0.01) and hypertensives Hypertensives had a lesser response than normotensives (r = −0.26, b = −8.3, P < 0.001). There was not a signif- (93 vs. 127 mL/min/1.73 m2). Women had a greater re- icant interaction between serum uric acid concentration sponse than men (112 vs. 97 mL/min/1.73 m2)(P = 0.02). and hypertension status (P = 0.78). Uric acid concentra- The serum uric acid concentration also correlated with tion independently predicted blunting of the renal vas- many baseline characteristics (Table 2). Basal RPF was cular response to Ang II [b = −5.3 (−8.1; −2.4), P < inversely correlated with serum uric acid concentration 0.001] (Table 3). Baseline RPF (b = 0.28, P < 0.001) (r = −0.30, P < 0.001) (Fig. 2). Hypertensives had a higher was the only other independent predictor. Age, gen- serum uric acid concentration then normotensives (5.8 vs. der, race, hypertension status, systolic and diastolic blood 4.6 mg/dL) (P < 0.001), while women had a lower serum pressure, BMI, serum glucose, serum insulin, serum total uric acid concentration then men (4.6 vs. 6.0 mg/dL) (P < cholesterol, serum triglycerides, serum HDL cholesterol, 0.001). BMI, systolic blood pressure, diastolic blood pres- PRA, creatinine clearance, and 24-hour urinary sodium 1468 Perlstein et al: Uric acid and the intrarenal RAS in humans

Table 2. Correlations with the renal plasma ﬂow (RPF) response to angiotensin II (Ang II) and the serum uric acid concentration RPF response to Ang II Serum uric acid rPvalue rPvalue

Basal RPF mL/min 1.73 m2 0.67 <0.001 −0.30 <0.001 Serum uric acid mg/dL −0.37 <0.001 NA NA Age years −0.35 <0.001 0.23 <0.001 Body mass index kg/m2 −0.36 <0.001 0.42 <0.001 Hypertension status HTN −34.9 <0.001 1.2 <0.001 Systolic blood pressure mm Hg −.034 <0.001 0.26 <0.001 Diastolic blood pressure mm Hg −0.33 <0.001 0.27 <0.001 Serum triglycerides mg/dL −0.32 <0.001 0.47 <0.001 Serum HDL mg/dL 0.18 0.008 0.40 <0.001 Gender female 14.9 0.02 1.44 <0.001 Serum insulin uU/mL −0.13 0.07 0.27 0.002 Race black 16.7 0.08 0.71 0.04 Serum total cholesterol mg/dL −0.12 0.09 0.23 0.004 PRA ng Ang I/mL/sec −0.03 0.25 0.13 0.33 Creatinine clearance mL/min −0.06 0.31 0.11 0.05 24-hour urine sodium mmol −0.05 0.4 0.09 0.14 Serum glucose mg/dL −0.07 0.69 0.09 0.99

Abbreviations are: HTN, hypertension; PRA, plasma renin activity; HDL, high-density lipoprotein. Pearson or Spearman correlations presented. For discrete variables, mean difference is reported. Statistical signiﬁcance was determined by univariate linear regression.

Table 3. Final model for predicting the renal plasma ﬂow (RPF) response to angiotensin II (Ang II) Regression coefﬁcient 95% CI P value Basal RPF 0.29 [0.24; 0.33] <0.001 2 mg/dL mL/min/1.73 m Uric acid mg/dL −5.3 [−8.1; −2.4] <0.001

Multivariable linear regression determined independent predictors of the RPF response to Ang II. Variables considered were age, gender, race, hypertension

Uric acid, status, systolic and diastolic blood pressure, body mass index, creatinine clearance, serum uric acid, basal renal plasma ﬂow, 24-hour urinary sodium excretion, seurm glucose, serum insulin, serum cholesterol, serum triglycerides,

246810 serum high-density lipoprotein (HDL) and plasma renin activity.

300 400 500 600 700 800 Basal RPF, mL/min/1.73m2 As described earlier, women had a lower serum uric acid Fig. 2. Serum uric acid is negatively correlated with baseline renal plasma flow (RPF) (r = −0.30, P < 0.001). concentration and a greater RPF response to Ang II. Pre- diction lines of the RPF response to Ang II among men and women are superimposed. In accord with this, the in- excretion were not independently associated with the teraction term between gender and serum uric acid con- RPF response to Ang II. A multivariable model sub- centration was not significant (P = 0.93). stituting basal renal vascular resistance index (diastolic blood pressure/RPF) for basal RPF yielded a similar effect estimate for serum uric acid (b = −5.3, P = DISCUSSION 0.001). No variable had a significant confounding ef- Whether uric acid contributes directly to hyperten- fect. Site did not influence the relationship between sion and renal disease in humans remains unresolved. A serum uric acid level and the RPF to Ang II. Di- recently developed animal model of hyperuricemia has agnostics did not reveal any observation with signif- provided compelling data suggesting that uric acid can icant leverage or influence. The interaction term for contribute to hypertension and nephropathy [15]. The race and serum uric acid was not significant (P = experimental model employs oxonic acid, an inhibitor of 0.65). uricase, causing elevation of the serum uric acid concen- We explored in greater depth whether gender had an tration but not sufficiently so as to cause crystal forma- effect on the relationship between serum uric acid con- tion. The oxonic acid–treated rat develops hypertension centration and the RPF response to Ang II. Figure 3 that corrects with hypouricemic therapy [5]. Independent presents the relationship between the serum uric acid of the rise in blood pressure, afferent arteriolopathy [6] concentration and the RPF to Ang II in men and women. and glomerular hypertrophy [7] are seen. Additionally, Perlstein et al: Uric acid and the intrarenal RAS in humans 1469

been attributed to either renal vascular abnormalities [3] or increased proximal tubule sodium resorption [4]. Hy- 2 perinsulinemia secondary to insulin resistance has been suggested as a cause of increased proximal tubule urate resorption [20, 21]. In our analysis the serum uric acid concentration predicted the RPF response to Ang II independently of both baseline RPF and serum insulin levels. 0 mL/min/1.73m We found it revealing that basal RPF and serum insulin

RPF response to Ang II, levels accounted for only 11% of the variation in serum

− 100246810 100 200 300 uric acid concentration, suggesting that these factors do Uric acid, mg/dL not have a dominant role in uric acid homeostasis. We examined specifically if gender based differences Men Women may have accounted for our observations, as women Predicted response Predicted response men women had lower serum uric acid concentrations and have been found to have increased renal responsiveness to exoge- Fig. 3. The observed and predicted renal plasma flow (RPF) response nous Ang II [22, 23]. We found that the relationship be- to angiotensin II (Ang II) plotted against the serum uric acid level in tween the serum uric acid concentration and the RPF women and men. Women tend to have a higher serum uric acid level and a higher RPF to Ang II than men. The prediction lines are overlapping, response to Ang II was not different in men and women. indicating that the relationship between the RPF response to Ang II The possibility that uric acid is associated with in- and the serum uric acid level is essentially identical in men and women. trarenal RAS activation in humans may provide insight into several observations that have been made, given that Ang II is strongly implicated in the pathogenesis of hy- the kidney exhibits a pattern of interstitial injury consis- pertension and nephropathy [24]. Hyperuricemia is an tent with exposure to Ang II [5, 16]. Renin is increased in independent predictor of the development of hyperten- the kidney of the hyperuricemic rat, and ACE inhibition sion [25] and is highly specific for essential hypertension ameliorates the renal injury [6]. These studies suggest the among pediatric patients [26]. Uric acid independently existence of a uric acid–mediated nephropathy,and impli- predicts risk for renal insufficiency among subjects with cate uric acid–induced activation of the intrarenal RAS normal renal function [27] and the progression of IgA as a key mediator of the renal damage. The mechanism nephropathy [28]. by which uric acid increases RAS activity is not clear. It is interesting to speculate that activation of the in- We have used the renal vasoconstrictor response to trarenal RAS might not be the primary mechanism re- exogenous Ang II as an indirect measure of intrarenal sponsible for what we have found. Changes in nitric oxide RAS activation in humans [17]. Multiple lines of evi- synthase (NOS) activity can influence vascular respon- dence indicate that this response is inversely correlated siveness to Ang II [5], and decreased NOS expression was with endogenous RAS activity [9–12]. The response is observed in the hyperuricemic rat [29]. Also, it is possible blunted during low sodium balance when endogenous that an association of uric acid with the intrarenal RAS RAS activity is greater [10]. The response to Ang II dur- could be driven by Ang II decreasing uric acid clearance ing low sodium balance is inversely correlated with the [30] or increasing xanthine oxidase activity [32]. How- vasodilator response to an ACE inhibitor[12]. ACE inhi- ever, pharmacologic interruption of Ang II activity is not bition enhances renal vascular responsiveness to Ang II significantly hypouricemic [33], suggesting that RAS ac- [18]. More recently we have found that variation within tivation is not a major determinant of hyperuricemia. the angiotensinogen gene associated with increased an- This analysis is exploratory in nature. While back- giotensinogen expression predicts blunted renal vascular ground studies suggest uric acid activates the intrarenal responsiveness to exogenous Ang II [13, 19]. RAS, our study cannot determine causation. The serum In light of the work in experimental hyperuricemia, uric acid concentration was determined at the screening we examined serum uric acid in our subjects who have visit and not on the study day, though we feel this would received intravenous Ang II under carefully controlled likely bias our result toward the null hypothesis. We could conditions. We found that the serum uric acid concentra- not test if the relationship of serum uric acid to blunted tion independently predicted blunted renal vascular re- renal vascular responsiveness is specific to Ang II. While sponsiveness to Ang II. Our result is consistent with the in our analysis we tested for confounding, interaction, observation in animals that hyperuricemia is associated leverage and influence, we acknowledge the assumptions with activation of the intrarenal RAS. and limitations of multivariable regression as an analytic Studies in humans have largely concluded that hype- tool. We have tested the renal vascular response to Ang II ruricemia reflects and does not contribute to renal dys- and therefore only have an indication of intrarenal vas- function. In particular, elevation in serum uric acid has cular RAS activity. Finally, although we have included 1470 Perlstein et al: Uric acid and the intrarenal RAS in humans baseline RPF as a predictor in our multivariable model, fluence of salt intake on adrenal glomerulosa and renal vascular we acknowledge that we cannot totally dissociate the responses to angiotensin II in normal man. J Clin Invest 54:34–42, 1974 serum uric acid level from renal hemodynamics. The 11. HOLLENBERG NK, WILLIAMS GH, TAUB KJ, et al: Renal vascular re- strengths of this study are its biologic plausibility, large sponse to interruption of the renin-angiotensin system in normal sample size, accounting for relevant confounders, and man. Kidney Int 12:285–293, 1977 12. FISHER ND, PRICE DA, LITCHFIELD WR, et al: Renal response to cap- carefully controlled experimental conditions. topril reflects state of local renin system in healthy humans. Kidney We have found that the serum uric acid level predicts Int 56:635–641, 1999 blunted renal vascular responsiveness to Ang II in hu- 13. HOPKINS PN, LIFTON RP, HOLLENBERG NK, et al: Blunted renal vascular response to angiotensin II is associated with a common variant mans. These data suggest that uric acid is associated with of the angiotensinogen gene and obesity. J Hypertens 14:199–207, an activated intrarenal RAS and therefore may provide 1996 insight into the relationship between the serum uric acid 14. RAJI A, WILLIAMS GH, JEUNEMAITRE X, et al: Insulin resistance in hypertensives: Effect of salt sensitivity, renin status and sodium intake. level and the risk for hypertension and nephropathy. Fur- J Hypertens 19:99–105, 2001 ther investigation into the relationship between uric acid 15. JOHNSON RJ, KANG DH, FEIG D, et al:Isthere a pathogenetic role and the intrarenal RAS is warranted. for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41:1183–1190, 2003 16. LOMBARDI D, GORDON KL, POLINSKY P, et al: Salt-sensitive hypertension develops after short-term exposure to Angiotensin II. Hy- pertension 33:1013–1019, 1999 ACKNOWLEDGMENTS 17. WILLIAMS GH, DLUHY RG, LIFTON RP, et al: Non-modulation as This research was supported by the following grants: National Insti- an intermediate phenotype in essential hypertension. Hypertension tutes of Health grants HL47651, HL59424, DK63214, Specialized Cen- 20:788–796, 1992 ter of Research in Hypertension from the National Heart, Lung and 18. OSEI SY, PRICE DA, FISHER ND, et al: Hyperglycemia and Blood Institute (HL55000), National Center for Research Resources angiotensin-mediated control of the renal circulation in healthy hu- (General Clinical Research Centers) in Boston (M01 RR 02635), Van- mans. Hypertension 33:559–564, 1999 derbilt (M01 RR 00095), and Salt Lake City (M01 RR 00064). Dr. Gu- 19. HOPKINS PN, HUNT SC, JEUNEMAITRE X, et al: Angiotensinogen geno- mieniak and Dr. Perlstein were in part supported by the NIH Training type affects renal and adrenal responses to angiotensin II in essential grant, T32 HL007609 and NIH (NHLBI) K30 grant HL04095-04. We hypertension. Circulation 105:1921–1927, 2002 gratefully acknowledge the assistance of the dietary, nursing, adminis- 20. FACCHINI F, CHEN YD, HOLLENBECK CB, et al: Relationship be- trative, and laboratory staffs of the three clinical research centers. tween resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 266:3008– Reprint requests to Todd S. Perlstein, Endocrinology Division, 221 3011, 1991 Longwood Avenue RFB-2, Boston, MA, 02115. 21. 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