Hypertension. 2001;38:1101-1106
doi: 10.1161/hy1101.092839
doi: 10.1161/hy1101.092839
(Hypertension. 2001;38:1101.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism
From the Division of Nephrology, University of Washington Medical Center (M.M., J.H., Y.-G.K., J.A.J., D.-H.K., K.L.G., R.J.J.), Seattle; the Division of Nephrology, Baylor College of Medicine (M.M., D.-H.K., R.J.J.), Houston, Tex; Queen Mary Hospital (H.Y.L.), Hong Kong, China; and Merck Inc (S.K.), West Point, Pa.
Correspondence to Marilda Mazzali, MD, Division of Nephrology, 1275 Smith, 6550 Fannin St, Houston TX 77030. E-mail m_mazzali{at}hotmail.com
Abstract—— 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 complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (r=0.75, n=69), with a 10–mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase.
Key Words: uric acid • hypertension renal • renin-angiotensin system • nitric oxide
This article has been cited by other articles:
 |
|
 |
|
  J. T. Park, D. K. Kim, T. I. Chang, H. W. Kim, J. H. Chang, S. Y. Park, E. Kim, S.-W. Kang, D.-S. Han, and T.-H. Yoo Uric acid is associated with the rate of residual renal function decline in peritoneal dialysis patients Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3520 - 3525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimada, R. J. Johnson, W. S. May Jr, V. Lingegowda, P. Sood, T. Nakagawa, Q. C. Van, B. Dass, and A. A. Ejaz A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome Nephrol. Dial. Transplant., October 1, 2009; 24(10): 2960 - 2964. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kosugi, T. Nakayama, M. Heinig, L. Zhang, Y. Yuzawa, L. G. Sanchez-Lozada, C. Roncal, R. J. Johnson, and T. Nakagawa Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice Am J Physiol Renal Physiol, August 1, 2009; 297(2): F481 - F488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Bainbridge, J.-S. Deng, and J. M. Roberts Increased Xanthine Oxidase in the Skin of Preeclamptic Women Reproductive Sciences, May 1, 2009; 16(5): 468 - 478. [Abstract] [PDF]
|
|
|
|
 |
|
 J. P. Forman, H. Choi, and G. C. Curhan Fructose and Vitamin C Intake Do Not Influence Risk for Developing Hypertension J. Am. Soc. Nephrol., April 1, 2009; 20(4): 863 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Johnson, S. E. Perez-Pozo, Y. Y. Sautin, J. Manitius, L. G. Sanchez-Lozada, D. I. Feig, M. Shafiu, M. Segal, R. J. Glassock, M. Shimada, et al. Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes? Endocr. Rev., February 1, 2009; 30(1): 96 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Forman, H. Choi, and G. C. Curhan Uric Acid and Insulin Sensitivity and Risk of Incident Hypertension Arch Intern Med, January 26, 2009; 169(2): 155 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Bataille, J. Goldmeyer, and J. L. Renfro Avian renal proximal tubule epithelium urate secretion is mediated by Mrp4 Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R2024 - R2033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Mohandas and R. J. Johnson Uric Acid Levels Increase Risk for New-Onset Kidney Disease J. Am. Soc. Nephrol., December 1, 2008; 19(12): 2251 - 2253. [Full Text] [PDF]
|
|
|
|
 |
|
 D. I. Feig, D.-H. Kang, and R. J. Johnson Uric Acid and Cardiovascular Risk N. Engl. J. Med., October 23, 2008; 359(17): 1811 - 1821. [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, V. Soto, E. Tapia, C. Avila-Casado, Y. Y. Sautin, T. Nakagawa, M. Franco, B. Rodriguez-Iturbe, and R. J. Johnson Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1134 - F1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. I. Feig, B. Soletsky, and R. J. Johnson Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized Trial JAMA, August 27, 2008; 300(8): 924 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Weiner, H. Tighiouart, E. F. Elsayed, J. L. Griffith, D. N. Salem, and A. S. Levey Uric Acid and Incident Kidney Disease in the Community J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1204 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. T. Rosolowsky, L. H. Ficociello, N. J. Maselli, M. A. Niewczas, A. L. Binns, B. Roshan, J. H. Warram, and A. S. Krolewski High-Normal Serum Uric Acid Is Associated with Impaired Glomerular Filtration Rate in Nonproteinuric Patients with Type 1 Diabetes Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 706 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, E. Tapia, V. Soto, C. Avila-Casado, M. Franco, L. Zhao, and R. J. Johnson Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1179 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, E. Tapia, P. Bautista-Garcia, V. Soto, C. Avila-Casado, I. P. Vega-Campos, T. Nakagawa, L. Zhao, M. Franco, and R. J. Johnson Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome Am J Physiol Renal Physiol, April 1, 2008; 294(4): F710 - F718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Kutzing and B. L. Firestein Altered Uric Acid Levels and Disease States J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J Johnson, M. S Segal, Y. Sautin, T. Nakagawa, D. I Feig, D.-H. Kang, M. S Gersch, S. Benner, and L. G Sanchez-Lozada Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease Am. J. Clinical Nutrition, October 1, 2007; 86(4): 899 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Reungjui, C. A. Roncal, W. Mu, T. R. Srinivas, D. Sirivongs, R. J. Johnson, and T. Nakagawa Thiazide Diuretics Exacerbate Fructose-Induced Metabolic Syndrome J. Am. Soc. Nephrol., October 1, 2007; 18(10): 2724 - 2731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Roncal, W. Mu, S. Reungjui, K. M. Kim, G. N. Henderson, X. Ouyang, T. Nakagawa, and R. J. Johnson Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1391 - F1396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. F. Panoulas, H. J. Milionis, K. M. J. Douglas, P. Nightingale, M. D. Kita, R. Klocke, M. S. Elisaf, and G. D. Kitas Association of serum uric acid with cardiovascular disease in rheumatoid arthritis Rheumatology, September 1, 2007; 46(9): 1466 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Choi and G. Curhan Independent Impact of Gout on Mortality and Risk for Coronary Heart Disease Circulation, August 21, 2007; 116(8): 894 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, E. Tapia, R. Lopez-Molina, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, J. Herrera-Acosta, and M. Franco Effects of acute and chronic L-arginine treatment in experimental hyperuricemia Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1238 - F1244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Iwanaga, M. Sato, T. Maeda, T. Ogihara, and I. Tamai Concentration-Dependent Mode of Interaction of Angiotensin II Receptor Blockers with Uric Acid Transporter J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 211 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Ejaz, W. Mu, D.-H. Kang, C. Roncal, Y. Y. Sautin, G. Henderson, I. Tabah-Fisch, B. Keller, T. M. Beaver, T. Nakagawa, et al. Could Uric Acid Have a Role in Acute Renal Failure? Clin. J. Am. Soc. Nephrol., January 1, 2007; 2(1): 16 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Roncal, W. Mu, B. Croker, S. Reungjui, X. Ouyang, I. Tabah-Fisch, R. J. Johnson, and A. Ahsan Ejaz Effect of elevated serum uric acid on cisplatin-induced acute renal failure Am J Physiol Renal Physiol, January 1, 2007; 292(1): F116 - F122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Forman, H. Choi, and G. C. Curhan Plasma Uric Acid Level and Risk for Incident Hypertension Among Men J. Am. Soc. Nephrol., January 1, 2007; 18(1): 287 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, E. Tapia, A. Jimenez, P. Bautista, M. Cristobal, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, et al. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats Am J Physiol Renal Physiol, January 1, 2007; 292(1): F423 - F429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Cirillo, W. Sato, S. Reungjui, M. Heinig, M. Gersch, Y. Sautin, T. Nakagawa, and R. J. Johnson Uric Acid, the Metabolic Syndrome, and Renal Disease J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S165 - S168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Perlstein, O. Gumieniak, G. H. Williams, D. Sparrow, P. S. Vokonas, M. Gaziano, S. T. Weiss, and A. A. Litonjua Uric Acid and the Development of Hypertension: The Normative Aging Study Hypertension, December 1, 2006; 48(6): 1031 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Mellen, A. J. Bleyer, T. P. Erlinger, G. W. Evans, F. J. Nieto, L. E. Wagenknecht, M. R. Wofford, and D. M. Herrington Serum Uric Acid Predicts Incident Hypertension in a Biethnic Cohort: The Atherosclerosis Risk in Communities Study Hypertension, December 1, 2006; 48(6): 1037 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Price, Y. Y. Sautin, D. A. Long, L. Zhang, H. Miyazaki, W. Mu, H. Endou, and R. J. Johnson Human Vascular Smooth Muscle Cells Express a Urate Transporter J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1791 - 1795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Sanders Uric Acid: An Old Dog with New Tricks? J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1767 - 1768. [Full Text] [PDF]
|
|
|
|
|
|
M. C.P. Franco, D. M.J. Christofalo, A. L. Sawaya, S. A. Ajzen, and R. Sesso Effects of Low Birth Weight in 8- to 13-Year-Old Children: Implications in Endothelial Function and Uric Acid Levels Hypertension, July 1, 2006; 48(1): 45 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zoccali, R. Maio, F. Mallamaci, G. Sesti, and F. Perticone Uric Acid and Endothelial Dysfunction in Essential Hypertension J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1466 - 1471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Lee, Y.-G. Kim, Y.-H. Choi, W. Huh, D. J. Kim, and H. Y. Oh Serum Uric Acid Is Associated With Microalbuminuria in Prehypertension Hypertension, May 1, 2006; 47(5): 962 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. Feig, M. Mazzali, D.-H. Kang, T. Nakagawa, K. Price, J. Kannelis, and R. J. Johnson Serum Uric Acid: A Risk Factor and a Target for Treatment? J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S69 - S73. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, A. Nivorozhkin, and C. Szabo Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., March 1, 2006; 58(1): 87 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3553 - 3562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Roberts and H. S. Gammill Preeclampsia: Recent Insights Hypertension, December 1, 2005; 46(6): 1243 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Johnson, M. S. Segal, T. Srinivas, A. Ejaz, W. Mu, C. Roncal, L. G. Sanchez-Lozada, M. Gersch, B. Rodriguez-Iturbe, D.-H. Kang, et al. Essential Hypertension, Progressive Renal Disease, and Uric Acid: A Pathogenetic Link? J. Am. Soc. Nephrol., July 1, 2005; 16(7): 1909 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Hediger, R. J Johnson, H. Miyazaki, and H. Endou Molecular Physiology of Urate Transport Physiology, April 1, 2005; 20(2): 125 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Johnson, B. Rodriguez-Iturbe, T. Nakagawa, D.-H. Kang, D. I. Feig, and J. Herrera-Acosta Subtle Renal Injury Is Likely a Common Mechanism for Salt-Sensitive Essential Hypertension Hypertension, March 1, 2005; 45(3): 326 - 330. [Full Text] [PDF]
|
|
|
|
|
|
R. J. Johnson, D. I. Feig, J. Herrera-Acosta, and D.-H. Kang Resurrection of Uric Acid as a Causal Risk Factor in Essential Hypertension Hypertension, January 1, 2005; 45(1): 18 - 20. [Full Text] [PDF]
|
|
|
|
|
|
J. Sundstrom, L. Sullivan, R. B. D'Agostino, D. Levy, W. B. Kannel, and R. S. Vasan Relations of Serum Uric Acid to Longitudinal Blood Pressure Tracking and Hypertension Incidence Hypertension, January 1, 2005; 45(1): 28 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Alper Jr, W. Chen, L. Yau, S. R. Srinivasan, G. S. Berenson, and L. L. Hamm Childhood Uric Acid Predicts Adult Blood Pressure: The Bogalusa Heart Study Hypertension, January 1, 2005; 45(1): 34 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Berry and J. M. Hare Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications J. Physiol., March 15, 2004; 555(3): 589 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Oparil, M. A. Zaman, and D. A. Calhoun Pathogenesis of Hypertension Ann Intern Med, November 4, 2003; 139(9): 761 - 776. [Full Text] [PDF]
|
|
|
|
|
|
D. I. Feig and R. J. Johnson Hyperuricemia in Childhood Primary Hypertension Hypertension, September 1, 2003; 42(3): 247 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kanellis and R. J. Johnson Editorial Comment--Elevated Uric Acid and Ischemic Stroke: Accumulating Evidence That It Is Injurious and Not Neuroprotective Stroke, August 1, 2003; 34(8): 1956 - 1957. [Full Text] [PDF]
|
|
|
|
|
|
C. J. Weir, S. W. Muir, M. R. Walters, and K. R. Lees Serum Urate as an Independent Predictor of Poor Outcome and Future Vascular Events After Acute Stroke Stroke, August 1, 2003; 34(8): 1951 - 1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. T. Rott and C. A. Agudelo Gout JAMA, June 4, 2003; 289(21): 2857 - 2860. [Full Text] [PDF]
|
|
|
|
 |
|
 T Bardin Fenofibrate and losartan Ann Rheum Dis, June 1, 2003; 62(6): 497 - 498. [Full Text] [PDF]
|
|
|
|
|
|
R. J. Johnson, D.-H. Kang, D. Feig, S. Kivlighn, J. Kanellis, S. Watanabe, K. R. Tuttle, B. Rodriguez-Iturbe, J. Herrera-Acosta, and M. Mazzali Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease? Hypertension, June 1, 2003; 41(6): 1183 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kanellis, S. Watanabe, J. H. Li, D. H. Kang, P. Li, T. Nakagawa, A. Wamsley, D. Sheikh-Hamad, H. Y. Lan, L. Feng, et al. Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2 Hypertension, June 1, 2003; 41(6): 1287 - 1293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hare and R. J. Johnson Uric Acid Predicts Clinical Outcomes in Heart Failure: Insights Regarding the Role of Xanthine Oxidase and Uric Acid in Disease Pathophysiology Circulation, April 22, 2003; 107(15): 1951 - 1953. [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Kang, T. Nakagawa, L. Feng, S. Watanabe, L. Han, M. Mazzali, L. Truong, R. Harris, and R. J Johnson A Role for Uric Acid in the Progression of Renal Disease J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2888 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Sanchez-Lozada, E. Tapia, C. Avila-Casado, V. Soto, M. Franco, J. Santamaria, T. Nakagawa, B. Rodriguez-Iturbe, R. J. Johnson, and J. Herrera-Acosta Mild hyperuricemia induces glomerular hypertension in normal rats Am J Physiol Renal Physiol, November 1, 2002; 283(5): F1105 - F1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Watanabe, D.-H. Kang, L. Feng, T. Nakagawa, J. Kanellis, H. Lan, M. Mazzali, and R. J. Johnson Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity Hypertension, September 1, 2002; 40(3): 355 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mazzali, J. Kanellis, L. Han, L. Feng, Y.-Y. Xia, Q. Chen, D.-H. Kang, K. L. Gordon, S. Watanabe, T. Nakagawa, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism Am J Physiol Renal Physiol, June 1, 2002; 282(6): F991 - F997. [Abstract] [Full Text] [PDF]
|
|