Clinical implications of the biological ambivalence of uric acid

Uric acid has historically been viewed as an inert waste product of purine metabolism, just like urea for proteins, able to crystallize at high concentrations, thus causing gouty arthritis and renal stones. In recent years, however, growing scientific evidence demonstrated that uric acid is not biologically inert but may also exert a wide array of effects including pro- and anti-oxidant actions, stimulation of inflammation and activation of the innate immune response [ [1] Johnson R.J. Bakris G.L. Borghi C. Chonchol M.B. Feldman D. Lanaspa M.A. et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the national kidney foundation. Am J Kidney Dis. 2018; 71: 851-865https://doi.org/10.1053/j.ajkd.2017.12.009 Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar , [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar ]. In this regard, the relative high levels of uric acid in humans has raised questions about its evolutionary advantages during hominid evolution [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [3] Andrews P. Johnson R.J. Evolutionary basis for the human diet: consequences for human health. J Intern Med. 2020; 287: 226-237https://doi.org/10.1111/joim.13011 Crossref PubMed Scopus (27) Google Scholar ]. In most mammals, uric acid is degraded by uricase to allantoin. However, during the mid-Miocene there were mutations involving the promoter region of uricase gene leading to a stepwise loss of this enzymatic activity [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar ]. As a consequence, serum uric acid (SUA) levels raised from 1 to 2 mg/dL, a concentration found in primates that still carry uricase, to 3–4 mg/dL, a concentration still observable in humans living on native diets [ [4] Johnson R.J. Titte S. Cade J.R. Rideout B.A. Oliver W.J. Uric acid, evolution and primitive cultures. Semin Nephrol. 2005; 25: 3-8https://doi.org/10.1016/j.semnephrol.2004.09.002 Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar ]. Among the various hypotheses that have been proposed to explain the potential evolutionary advantages deriving by an increase in SUA levels, one of the most reliable hypotheses is that it may provide key antioxidant functions contributing to prevent vascular disease and contrasting the oxidative stress associated with aging [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar ]. Indeed, uric acid alone contributes to about half of the antioxidant capacity of human plasma and its antioxidant properties are comparable to those of ascorbic acid [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar ]. This effect could have been particular useful during the Miocene era for hominids who were unable to biosynthesize vitamin C as a key gene involved in vitamin C production had been mutated 20–40 million years earlier. In addition, uric acid might amplify the ability to store fat and glycogen from fruit sugar [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [3] Andrews P. Johnson R.J. Evolutionary basis for the human diet: consequences for human health. J Intern Med. 2020; 287: 226-237https://doi.org/10.1111/joim.13011 Crossref PubMed Scopus (27) Google Scholar ]. Indeed, fructose metabolism leads to a depletion of intracellular energy, triggering adenine nucleotide degradation and uric acid formation which, in turn, stimulates fat accumulation and insulin resistance [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [3] Andrews P. Johnson R.J. Evolutionary basis for the human diet: consequences for human health. J Intern Med. 2020; 287: 226-237https://doi.org/10.1111/joim.13011 Crossref PubMed Scopus (27) Google Scholar ]. Thus, the uricase mutation resulted in a greater production of uric acid in response to fructose, leading to a greater increase of liver fat accumulation and gluconeogenesis, thereby favoring survival during a period of famine or stress [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [3] Andrews P. Johnson R.J. Evolutionary basis for the human diet: consequences for human health. J Intern Med. 2020; 287: 226-237https://doi.org/10.1111/joim.13011 Crossref PubMed Scopus (27) Google Scholar ]. Uric acid can also help to preserve sodium retention leading to a rise in blood pressure [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [5] Watanabe S. Kang D.H. Feng L. Nakagawa T. Kanellis J. Lan H. et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002; 40: 355-360https://doi.org/10.1161/01.hyp.0000028589.66335.aa Crossref PubMed Scopus (0) Google Scholar ] and, thus, might have played a role in accelerating the development of bipedal locomotion during an evolutionary period in which food was scarce and sodium intake low [ [2] Johnson R.J. Sautin Y.Y. Oliver W.J. Roncal C. Mu W. Gabriela Sanchez-Lozada L. et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?. J Comp Physiol B. 2009; 179: 67-76https://doi.org/10.1007/s00360-008-0291-7 Crossref PubMed Scopus (115) Google Scholar , [5] Watanabe S. Kang D.H. Feng L. Nakagawa T. Kanellis J. Lan H. et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002; 40: 355-360https://doi.org/10.1161/01.hyp.0000028589.66335.aa Crossref PubMed Scopus (0) Google Scholar ]. From an evolutionary perspective, the uricase mutation, by amplifying the effects of fructose to increase fat stores, blood pressure and insulin resistance may have acted as a “thrifty gene”, providing survival advantage for hominids in seasonal habitats during times of food shortage but becoming harmful with ample access to food [ [1] Johnson R.J. Bakris G.L. Borghi C. Chonchol M.B. Feldman D. Lanaspa M.A. et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the national kidney foundation. Am J Kidney Dis. 2018; 71: 851-865https://doi.org/10.1053/j.ajkd.2017.12.009 Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar ].