Download PDF
CC BY-NC-ND 4.0 · Ibnosina Journal of Medicine and Biomedical Sciences 2023; 15(03): 110-116
DOI: 10.1055/s-0043-1770929
Review Article

The Impact of Uric Acid on Human Health: Beyond Gout and Kidney Stones

Nasr Anaizi
1   Department of Physiology, Faculty of Medicine, University of Benghazi, Benghazi, Libya
› Author Affiliations Funding and Sponsorship None.
› Further Information
Also available at
   Permissions and Reprints

Abstract

In most primates, including humans, uric acid (UA) is the end product of purine metabolism due to the loss of hepatic uricase activity during evolution. This loss resulted in higher serum urate concentrations (3.5–7.5 mg/dL) than normally observed in other mammals (0.05–2 mg/dL). About 70% of the daily urate burden is eliminated via the kidneys and the remainder via the intestines, where gut bacteria break it down. Urate is freely filtered through the glomerular capillaries, and most of the filtered urate is reabsorbed so that only an amount equivalent to about 10% of the filtered load is excreted in the urine. Virtually all of the renal urate reabsorption takes place in proximal convoluted tubules. Many transport proteins connected with urate have been identified. However, the best studied are URAT1 and GLUT9, which function in concert to translocate urate from the proximal tubule lumen to the peritubular fluid, the first in the apical membrane and the second in the basolateral membrane. Genetic mutations, as well as drugs that alter the function of these transporters, can affect urate homeostasis resulting in abnormal serum levels, which may, in turn, be involved in the pathogenesis of chronic metabolic and inflammatory diseases, including most features of the metabolic syndrome, hypertension, cardiovascular disease, and chronic kidney disease. Several mechanisms are thought to provide the link between urate and these disorders, including reactive oxygen species (oxidative stress) and both acute and chronic inflammation. This mini-review summarizes the basic human biology of UA and its association with and potential involvement in developing chronic diseases beyond gout and nephrolithiasis.

Keywords

Uric acid - metabolism - hyperuricemia - pathogenesis of disease - oxidative stress - chronic inflammation - insulin resistance - essential hypertension - chronic kidney disease

Compliance with Ethical Principles

No ethical approval is required for the review article type of study.




Publication History

Article published online:
13 July 2023

© 2023. The Libyan Biotechnology Research Center. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Richet G. The chemistry of urinary stones around 1800: a first in clinical chemistry. Kidney Int 1995; 48 (03) 876-886
    CrossrefPubMedSearch in Google Scholar
  • 2 Haig A. Uric Acid as a Factor in the Causation of Disease. 4th ed.. London, UK: J & A Churchill; 1897
    Search in Google Scholar
  • 3 Lanaspa MA, Sanchez-Lozada LG, Cicerchi C. et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 2012; 7 (10) e47948
    CrossrefPubMedSearch in Google Scholar
  • 4 Johnson RJ. Gout: the poster child for activation of the survival switch. In: Nature Wants Us to Be Fat. 1st ed.. Dallas, TX: BenBella Books, Inc.; 2022
    Search in Google Scholar
  • 5 Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edition: 6th Edition. 2017. Publisher: Elsevier;
    Search in Google Scholar
  • 6 Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis 2012; 19 (06) 358-371
    CrossrefPubMedSearch in Google Scholar
  • 7 Woodward OM, Köttgen A, Köttgen M. ABCG2 and hyperuricemia. N Engl J Med 2014; 371 (23) 2233-2234
    PubMedSearch in Google Scholar
  • 8 Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 2013; 34 (2-3): 121-138
    CrossrefPubMedSearch in Google Scholar
  • 9 Ruiz A, Gautschi I, Schild L, Bonny O. Human mutations in SLC2A9 (Glut9) affect transport capacity for urate. Front Physiol 2018; 9: 476
    CrossrefPubMedSearch in Google Scholar
  • 10 Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981; 78 (11) 6858-6862
    CrossrefPubMedSearch in Google Scholar
  • 11 Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 1989; 86 (16) 6377-6381
    CrossrefPubMedSearch in Google Scholar
  • 12 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008; 27 (06) 608-619
    CrossrefPubMedSearch in Google Scholar
  • 13 Johnson RJ, Rodriguez-Iturbe B, Kang DH, Feig DI, Herrera-Acosta J. A unifying pathway for essential hypertension. Am J Hypertens 2005; 18 (03) 431-440
    CrossrefPubMedSearch in Google Scholar
  • 14 Gonçalves DLN, Moreira TR, da Silva LS. A systematic review and meta-analysis of the association between uric acid levels and chronic kidney disease. Sci Rep 2022; 12 (01) 6251
    CrossrefPubMedSearch in Google Scholar
  • 15 Li R, Jia Z, Trush MA. Defining ROS in biology and medicine. React Oxyg Species (Apex) 2016; 1 (01) 9-21
    PubMedSearch in Google Scholar
  • 16 Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol 2015; 4: 180-183
    CrossrefPubMedSearch in Google Scholar
  • 17 Kimura Y, Tsukui D, Kono H. Uric acid in inflammation and the pathogenesis of atherosclerosis. Int J Mol Sci 2021; 22 (22) 12394
    CrossrefPubMedSearch in Google Scholar
  • 18 Zheng Z, Wang G, Li L. et al. Transcriptional signatures of unfolded protein response implicate the limitation of animal models in pathophysiological studies. Environ Dis 2016; 1 (01) 24-30
    CrossrefPubMedSearch in Google Scholar
  • 19 Xie D, Zhao H, Lu J. et al. High uric acid induces liver fat accumulation via ROS/JNK/AP-1 signaling. Am J Physiol Endocrinol Metab 2021; 320 (06) E1032-E1043
    CrossrefPubMedSearch in Google Scholar
  • 20 Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440 (7081): 237-241 a.
    CrossrefPubMedSearch in Google Scholar
  • 21 Busso N, Ea HK. The mechanisms of inflammation in gout and pseudogout (CPP-induced arthritis). Reumatismo 2012; 63 (04) 230-237
    CrossrefPubMedSearch in Google Scholar
  • 22 Milanesi S, Verzola D, Cappadona F. et al. Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4. J Cell Physiol 2019; 234 (07) 10868-10876
    CrossrefPubMedSearch in Google Scholar
  • 23 Sirisinha S. Insight into the mechanisms regulating immune homeostasis in health and disease. Asian Pac J Allergy Immunol 2011; 29 (01) 1-14
    PubMedSearch in Google Scholar
  • 24 Kanbay M, Jensen T, Solak Y. et al. Uric acid in metabolic syndrome: From an innocent bystander to a central player. Eur J Intern Med 2016; 29: 3-8
    CrossrefPubMedSearch in Google Scholar
  • 25 Yu W, Xie D, Yamamoto T, Koyama H, Cheng J. Mechanistic insights of soluble uric acid-induced insulin resistance: insulin signaling and beyond. Rev Endocr Metab Disord 2023; 24 (02) 327-343
    CrossrefPubMedSearch in Google Scholar
  • 26 Johnson RJ, Merriman T, Lanaspa MA. Causal or noncausal relationship of uric acid with diabetes. Diabetes 2015; 64 (08) 2720-2722
    CrossrefPubMedSearch in Google Scholar
  • 27 He Y, Chen D, Xu JP. et al. Association between serum uric acid and hypertension in a large cross-section study in a Chinese population. J Cardiovasc Dev Dis 2022; 9 (10) 346
    PubMedSearch in Google Scholar
  • 28 Feig DI, Johnson RJ. The role of uric acid in pediatric hypertension. J Ren Nutr 2007; 17 (01) 79-83
    CrossrefPubMedSearch in Google Scholar
  • 29 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008; 300 (08) 924-932
    CrossrefPubMedSearch in Google Scholar
  • 30 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359 (17) 1811-1821
    CrossrefPubMedSearch in Google Scholar
  • 31 Mazzali M, Hughes J, Kim YGJ. et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001; 38 (05) 1101-1106
    CrossrefPubMedSearch in Google Scholar
  • 32 Khosla UM, Zharikov S, Finch JL. et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005; 67 (05) 1739-1742
    CrossrefPubMedSearch in Google Scholar
  • 33 Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013; 99 (11) 759-766
    CrossrefPubMedSearch in Google Scholar
  • 34 Lee TH, Chen JJ, Wu CY, Yang CW, Yang HY. Hyperuricemia and progression of chronic kidney disease: a review from physiology and pathogenesis to the role of urate-lowering therapy. Diagnostics (Basel) 2021; 11 (09) 1674
    CrossrefPubMedSearch in Google Scholar
  • 35 Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which?. Nephrol Dial Transplant 2013; 28 (09) 2221-2228
    CrossrefPubMedSearch in Google Scholar
  • 36 Bose B, Badve SV, Hiremath SS. et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 2014; 29 (02) 406-413
    CrossrefPubMedSearch in Google Scholar
  • 37 Polito L, Bortolotti M, Battelli MG, Bolognesi A. Chronic kidney disease: which role for xanthine oxidoreductase activity and products?. Pharmacol Res 2022; 184: 106407
    CrossrefPubMedSearch in Google Scholar