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

Uric Acid and Cell Metabolism

Cellular metabolism profile plays a role in immune cell differentiation and in their operation in physiologic and inflammatory processes.[67] Cell metabolism involves various enzyme-orchestrated chemical reactions that result in synthesis and degradation of molecules to fuel energy and building blocks for cells. Generally, in a simplistic way, pro-inflammatory cells, such as effector T cells and M1 macrophages, tend to use glycolysis while anti-inflammatory cells, such as M2 macrophages, memory CD8+ T cells and regulatory T cells utilize mitochondrial oxidative phosphorylation and fatty acid oxidation.[68] Changes in cell metabolism may reflect in cell phenotype and functionality. In some diseases, immune cells with impaired immune function appear to be equally metabolically compromised.[69]

The effect of sUA on cell metabolism is a still fairly unexplored field in contemporary research. Because metabolic reprogramming plays an important role in macrophage biology, and activated macrophages generate ROS as a microbicide mechanism,[70] we have proposed in a recent study that the mechanism underlying sUA-induced inflammation is dependent on redox state changes. We observed that sUA promotes mitochondrial modifications and increased mitochondrial ROS production by macrophages, and that such metabolic changes were accompanied by NLRP3 inflammasome activation and IL-1β production.[13] NLRP3 is a key molecule that connect inflammation and cellular metabolism. NLRP3 inflammasome and caspase-1 activation can directly regulate cellular metabolism by cleaving proteins involved in this process, for example sirtuin-1,[14] enzymes involved in glycolysis (glyceraldehyde-3-phosphate dehydrogenase, aldolase, enolase, triosephosphate isomerase, and pyruvate kinase),[15] and nuclear receptor PPARγ.[16]

In proximal tubular epithelial cells, growing evidence indicates that perturbations in fatty acid and glycolytic metabolism contribute to renal fibrosis by inducing pro-fibrotic mediators, apoptosis, lipotoxicity, and epithelial-to-mesenchymal transition.[71,72] How sUA modulates the metabolism of renal cells is still unclear. A recent study demonstrated that the liver kinase B1(LKB1)/AMP-activated protein kinase (AMPK)/mTOR pathway was the most abundantly enriched pathway in sUA-stimulated proximal tubular epithelial cells.[73] Although these data suggest a role for sUA in the metabolism of renal cells, further studies are needed to evaluate in a broader way how sUA-induced metabolic changes – and the associated inflammasome platforms – exert pathogenic or even cytoprotective effects in kidney tissue under injury.