Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity

Abstract

Abstract-Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.

Modulation of serum uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure

“…[4][5][6][7][8] At the same time, numerous studies have linked high serum UA levels with increased blood pressure. Hyperuricaemia has been shown to maintain blood pressure in rats on a low-salt diet (for a review see Watanabe et al 9 ). This raises the possibility that high UA levels may contribute to the pathogenesis of hypertension in humans, a concept supported by a number of studies showing an association between elevated serum UA levels and high blood pressure.…”

“…This raises the possibility that high UA levels may contribute to the pathogenesis of hypertension in humans, a concept supported by a number of studies showing an association between elevated serum UA levels and high blood pressure. [9][10][11] However most early studies were conducted either in rodent models, which have very different natural handling of the end purine metabolism, or in human populations already predisposed to vascular disorders, and thus do not provide a clear answer as to whether elevated serum UA is a cause or effect of such conditions. In this study, we used inosine, a natural metabolic precursor of UA, to raise serum urate levels in patients with MS to upper physiological levels of around 7-8 mg per 100 ml.…”

“…A number of animal and human studies have been reported in which increased serum UA levels were found to be associated not only with an increased risk for hypertension but also with a variety of cardiovascular diseases (reviewed in Watanabe et al, 9 Johnson et al, 10 and Mene and Punzo 11 ). For example, rats treated with the urate oxidase inhibitor oxonic acid show increases in both serum UA level and blood pressure.…”

“…7,8 An alternative hypothesis is that elevated serum urate evolved to help maintain blood pressure in lowsalt dietary conditions encountered by early hominoids during the Miocene epoch. 9 This function of UA would be undesirable in modern humans with our high-salt diet and may contribute to the epidemic of cardiovascular disease and hypertension that plagues modern societies. Indeed there is evidence suggesting a pathogenic role for high UA levels in the development of hypertension, vascular disease and renal disease (for a review, see Johnson et al 10 and Mene and Punzo 11 ).…”

Serum uric acid, the endothelium and hypertension: an association revisited

“…1 These occurred during the Miocene Era, some 18-22 million years ago. The first mutation is likely to have occurred when the Pongo (orangutan)/Gorilla/Pan (chimpanzee)/Homo (human) line split from other apes.…”