Uric Acid, Evolution and Primitive Cultures Richard J. Johnson,* Srinivas Titte,* J. Robert Cade,* Bruce A. Rideout, † and William J. Oliver ‡ Hypertension is epidemic and currently affects 25% of the world’s population and is a major cause of stroke, congestive heart failure, and end-stage renal disease. Interestingly, there is evidence that the increased frequency of hypertension is a recent event in human history and correlates with dietary changes associated with Westernization. In this article, we review the evidence that links uric acid to the cause and epidemiology of hypertension. Specifically, we review the evidence that the mutation of uricase that occurred in the Miocene that resulted in a higher serum uric acid in humans compared with most other mammals may have occurred as a means to increase blood pressure in early hominoids in response to a low-sodium and low-purine diet. We then review the evidence that the epidemic of hypertension that evolved with Westernization was associated with an in- crease in the intake of red meat with a marked increase in serum uric acid levels. Indeed, gout and hyperuricemia should be considered a part of the obesity, type 2 diabetes, and hypertension epidemic that is occurring worldwide. Although other mechanisms certainly contribute to the pathogenesis of hypertension, the possibility that serum uric acid level may have a major role is suggested by these studies. Semin Nephrol 25:3-8 © 2005 Elsevier Inc. All rights reserved. H ypertension is epidemic in industrialized nations, where it affects nearly 25% of the population, and is the major cause of stroke and congestive heart failure, and the second most common cause of end-stage renal disease. 1 Hy- pertension is also increasing in prevalence in developing countries, in association with the large-scale epidemics of diabetes and obesity. 2-4 Identifying the cause of primary hy- pertension has been a central focus of scientific research. Although there is clearly a genetic component, most studies suggest that difference in polygene expression only accounts for 20% to 30% of all hypertension. 5 Thus, emphasis has been placed on environmental factors such as diet (sodium, potassium, and calcium intake), maternal nutrition, stress, and other factors that can alter hormonal or sympathetic nervous system activity that modulates blood pressure. In this article we summarize evidence linking the epidemic of hypertension to uric acid. The Uricase Mutation in Human Evolution Uric acid is a product of purine metabolism that is generated during the enzymatic degradation of xanthine. When the enzyme is xanthine oxidase, both uric acid and superoxide anion are produced, whereas the reaction with xanthine de- hydrogenase releases uric acid and the reduced form of nic- otinamide-adenine dinucleotide. In most mammals, uric acid is degraded further by the enzyme uricase (also known as urate oxidase) to allantoin. Serum uric acid levels are there- fore low (0.5– 2.0 mg/dL) in most mammals. However, dur- ing the Miocene epoch (8 –20 million years ago) parallel mu- tations occurred in our hominoid ancestors that first affected the promoter region and later the whole gene, eventually resulting in complete loss of uricase. 6 As a consequence, hu- mans and the Great Apes have higher uric acid levels than most other mammals. In addition, some species of New World monkeys also lost uricase, and many Old World mon- keys have lower uricase activity than other mammals, 7 sug- gesting similar processes in these species. The stepwise loss of uricase may have allowed adaptation to the loss of this im- portant gene because the sudden knockout of uricase in mice is lethal owing to dramatic increases in serum uric acid levels that cause acute urate nephropathy and renal failure. 8 One likely adaptation was a decrease in xanthine oxidase activity because humans have only 1% activity of this enzyme com- *Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL. †Center for Reproduction of Endangered Species, Zoological Society of San Diego, San Diego CA. ‡Department of Pediatrics, University of Michigan, Ann Arbor, MI. Supported by National Institutes of Health grants HL-68607 and DK-52121. Address reprint requests to Richard J. Johnson, MD, Division of Nephrology, Hypertension, and Transplantation, PO Box 100024, University of Florida, Gainesville, FL 32610. E-mail: johnsrj@medicine.ufl.edu 3 0270-9295/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2004.09.002