Abstract and Introduction
Purpose of review: Uric acid is produced after purine nucleotide degradation, upon xanthine oxidase catalytic action. In the evolutionary process, humans lost uricase, an enzyme that converts uric acid into allantoin, resulting in increased serum uric acid levels that may vary according to dietary ingestion, pathological conditions, and other factors. Despite the controversy over the inflammatory role of uric acid in its soluble form, crystals of uric acid are able to activate the NLRP3 inflammasome in different tissues. Uric acid, therefore, triggers hyperuricemic-related disease such as gout, metabolic syndrome, and kidney injuries. The present review provides an overview on the role of uric acid in the inflammasome-mediated kidney damage.
Recent findings: Hyperuricemia is present in 20–35% of patients with chronic kidney disease. However, whether this increased circulating uric acid is a risk factor or just a biomarker of renal and cardiovascular injuries has become a topic of intense discussion. Despite these conflicting views, several studies support the idea that hyperuricemia is indeed a cause of progression of kidney disease, with a putative role for soluble uric acid in activating renal NLRP3 inflammasome, in reprograming renal and immune cell metabolism and, therefore, in promoting kidney inflammation/injury.
Summary: Therapies aiming to decrease uric acid levels prevent renal NLRP3 inflammasome activation and exert renoprotective effects in experimental kidney diseases. However, further clinical studies are needed to investigate whether reduced circulating uric acid can also inhibit the inflammasome and be beneficial in human conditions.
Uric acid is an organic compound of nitrogen, carbon, hydrogen, and oxygen produced after purine nucleotide degradation. The study of uric acid shed light on some evolutionary aspects of humans, as our ancestors lost the uricase gene. The primary consequence of such loss was the increase in serum levels of uric acid at approximately 3.02 to 6.72 mg/dl, 10 times more in comparison with other animals. Uricase loss brought some advantages throughout the evolutionary process, such as the better energy storage potential and an increase in the antioxidative ability. High uric acid levels, for instance, regulate enzymes associated with glucose and lipid metabolism. However, the absence of functional uricase also allowed for the appearance of some recently epidemiological relevant hyperuricemic-related diseases, such as gout, metabolic syndrome and kidney injury. All of these diseases are increasing in incidence and prevalence in both developed and developing countries.[4,5] Moreover, elevation in serum levels of uric acid leads to the formation and deposition of monosodium urate crystals, a remarkable event in the pathology of these hyperuricemic-related diseases.[6–9]
The monosodium urate crystals are phagocyted by cells of the immune system and, as they are not degraded by lysosomal enzymes, this may lead to lysosome rupture, ultimately leading to the activation and oligomerization of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing-3 (NLRP3) inflammasome and the release of interleukin-1β (IL-1β).[11,12] Uric acid, in its soluble form, on the other hand, does not activate NLRP3 into human macrophages, despite presenting an inflammatory role in murine cells. NLRP3 activation can directly regulate cellular metabolism by cleaving regulators of cellular metabolism, altering enzymes involved in glycolysis, and modulating nuclear receptor peroxisome proliferator-activated receptor (PPARγ). However, the exact role of uric acid in cell metabolism is not clearly known. Moreover, studies published over the past few years have demonstrated a role for the NLRP3 activation in the development of kidney inflammation and the development of renal fibrosis.[17,18]
In this Review, we discuss the implications of uricase loss and give special attention to the existent paradox between the oxidant/antioxidant role of uric acid. We critically address the controversy on the inflammatory and immune modulatory states triggered by uric acid. We additionally indicate the efforts and advances over the past decade to elucidate the role of hyperuricemia in the pathogenesis of renal diseases, and discuss emerging therapeutic strategies to manage hyperuricemic-related diseases.
Curr Opin Nephrol Hypertens. 2020;29(4):423-431. © 2020 Lippincott Williams & Wilkins