The Role of Uric Acid in Inflammasome-Mediated Kidney Injury

Tarcio Teodoro Braga; Orestes Foresto-Neto; Niels Olsen Saraiva Camara


Curr Opin Nephrol Hypertens. 2020;29(4):423-431. 

In This Article

Evolution and Uric Acid

Uric acid is produced upon xanthine oxidase catalytic action on xanthine and hypoxanthine, which in turn are generated after purine nucleotide metabolic breakdown. Purine nucleotides are derived from DNA, RNA, ATP, ADP, and AMP and also from other key compounds in global metabolism, such as FAD, coenzyme A, and S-adenosylmethionine.[19] Additionally, uric acid production is elevated in a context of hypoxia,[20] once hypoxanthine secretion is increased in hypoxic area.[21] Uric acid represents the main nitrogen excretion route for certain animals, such as birds and reptiles, whereas it is excreted in feces as a dry mass, an energetically costly process that has the advantage of reducing water loss, avoiding, therefore, dehydration.[22] In mammals, the main way of nitrogen excretion is through elimination of urea in urine, despite that higher primates (humans, chimpanzees, gorillas, orangutans and bonobos) also excrete uric acid in urine. The urine and serum levels of uric acid vary depending on the genetic, dietary ingestion, drugs consumption, physical exercise, and pathological conditions. In most mammals, the serum levels of uric acid range from 18 to 40 µM, whereas great apes exhibit serum levels between 180 and 400 µM, corresponding to 3.02 to 6.72 mg/dl.[1] Additionally, in human blood, uric acid concentration varies depending on the protein mass content.[23] Also, the normal excretion of uric acid in the urine is 250 to 750 mg/day, considering 1 l of urine is produced per day.

Differences in serum uric acid concentration among great apes and other mammals demonstrate an evolutionary process related to uric acid: the loss of uricase. Uricase, also known as urate oxidase, is an enzyme involved in purine catabolism that converts uric acid into allantoin.[2] Experiments performing the expression of uricase derived from different animals into human cells followed by their purification and posterior enzymatic activity measurement reveal that ancestral uricase have steadily decreased in activity since the last common ancestor of mammals.[24] Moreover, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes.[24] Uricase loss may be related to a survival advantage[25] because high levels of serum uric acid give rise to high-energy storage ability.[2] The loss of uricase activity in the period of global cooling by the end of the Oligocene[24,26,27] allowed our ancestors to better accumulate energy in the fatty acid form via the metabolism of fructose from fruits. The triacylglycerol content in human hepatocyte cells, for instance, is significantly increased through uric acid stimulus in a dose dependent manner.[28] Uric acid increases lipogenesis in hepatocytes through the inhibition of mitochondrial aconitase activity and the activation of ATP-citrate lyase.[28] Moreover, the murine intraperitoneal administration of uric acid improves the activity of complexes I, II, III, and V in the mitochondrial respiratory chain in ref..[29] Fossil studies showed that apes' ancestors were fruit eaters and when the rapid cooling at 15–12 millions of years ago occurred, the increased seasonality in Africa and Europe may have probably forced mutations in uric acid metabolism to allow them survive.[30]

It is noteworthy that inflammasome-related proteins are under evolutionary press in a context of pathogen-related diseases. The evolution of inflammasome inhibitors, for instance, suggests strong selection pressure for control over inflammasome activation.[31] However, the evolutionary process of inflammasome-related proteins also occurs in the absence of an infectious context. Changes in oxidative products may also have imposed a selective pressure on inflammasome receptors, even before the appearance of mammals. ROS are, for example, sense in plants[32] and a gradient of ROS is the apical signal directing wound healing in zebrafish.[33] In support of this, NLRP3 agonists used in basic research and clinical trials, including ATP and particulate activators, induce ROS and ROS blockade by chemical scavengers suppresses inflammasome activation.[34–39]

Mutations in uricase present in great apes are coincident with mutations in L-gulonolactone oxidase, an enzyme responsible for generating L-ascorbic acid (vitamin C), an important antioxidant molecule.[40] It is hypothesized that uric acid may have replaced L-ascorbic acid as an antioxidant molecule.[41,42] The antioxidant functions of uric acid rely on its high reactivity with singlet oxygen,[43] hydroxyl radicals, and various organic peroxides.[44,45] However, despite such protective role, there is an oxidant/antioxidant paradox related to uricase loss, once increased levels of uric acid are also related to oxidative processes.[46] The putative mechanisms for uric acid-related damage appear to be mediated by the development of mitochondrial oxidative stress and impairment of insulin-dependent stimulation of nitric oxide in endothelial cells. In addition, uric acid is directly related to comorbidities associated with obesity and metabolic syndrome,[47] whereas hyperuricemia is a common feature in obesity, chronic renal failure, metabolic syndrome, and type 2 diabetes patients.[48] High levels of serum uric acid lead to insulin resistance, fatty liver, and dyslipidemia in both fructose-dependent and fructose-independent models of metabolic syndrome.[48] The oxidant/antioxidant paradox and the inflammatory aspects of uric acid will be better explained in the next topics.