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

Crystals and Soluble Uric Acid

The physiological role of uric acid – acting as an alarmin or a cytoprotective agent – depends mainly on its solubility status. It was suggested that uric acid crystals, in different tissue and fluids body, present pro-inflammatory properties and can thus contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several pathologies. On the other hand, soluble uric acid (sUA) possesses antioxidant properties that might attenuate inflammatory responses.[9] It has been shown that sUA is unable to trigger the immune system in human cells, despite acting as inflammatory molecule in murine model.[13] Most uric acid circulates in the body fluids as the monosodium urate anion, and its concentrations normally approach the theoretical limit of serum monosodium urate solubility, at approximately 6.8 mg/dl.[49] The solubility of monosodium urate depends on the fluid pH (increasing with the rise in pH), the concentration of sodium and monosodium urate anion and also on the time of precipitation.[50] This can explain why uric acid is so highly soluble in urine (as much as 220 mg/dl of uric acid dissolved in an incubation period of 24 h at pH 7.0 in urine).[50]

In addition, the solubility state, the oxidant/antioxidant paradox of uric acid also depends on the location where uric acid can be found. This paradox relates to the soluble form of uric acid, acting either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell).[46] Once crystallized, on the other hand, uric acid can be sensed by the immune system,[51,52] in a location-independent way, behaving as a pro-oxidant molecule. Crystals of uric acid are able to induce proinflammatory cytokines, such as IL-1β,[52–54] to increase the production of reactive oxygen species (ROS), to stimulate chemotaxis and also to activate NF-κB and MAPK pathways.[55] A contrasting data, otherwise, shows that inhibition of ROS diminished the TLR2-induced priming of the NLRP3 inflammasome, but had no effect on crystals-induced activation.[56] Meanwhile, data show that hyperuricemia, in absence of crystals formation, can also modulate the inflammatory response. The hyperuricemic state is able to modulate the leukocyte response towards an inflammatory pattern through epigenetic modifications, including histone methylation.[7] In patients, hyperuricemia also leads to enhanced production of IL-1β and IL-6, and the concomitant reduction of IL-1Ra release.[7] However, it is possible that microcrystals can be formed in an undetectable way.