The Role of Uric Acid in Inflammasome-Mediated Kidney Injury

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

Disclosures

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

In This Article

Uric Acid and NLRP3 Inflammasome in Kidney Tissue Injuries

In the last few years, Johnson et al. have employed many efforts to elucidate the role of hyperuricemia in the pathogenesis of the cardiovascular and renal disease. They have shown that mild hyperuricemia activated the renin–angiotensin system and inhibited the intrarenal neuronal NO synthase expression in rats, promoting renal arteriolopathy without crystal formation.[85] Later, they demonstrated that increased uric acid levels in kidney tissue accelerated renal disease progression in rats underwent 5/6 renal ablation via mechanisms associated to hypertension and increase in renal COX-2.[86] However, the real mechanisms linking increased sUA and kidney damage remained to be clarified. Recent evidence shows that, like crystalline uric acid, sUA also activates renal NLRP3 inflammasome and promotes kidney damage has emerged[87–89] (Table 1).

In the unilateral ureter obstruction (UUO) model,[13] we showed that allopurinol, a xanthine oxidase inhibitor widely employed in the treatment of hyperuricemia, reduced the renal content of sUA and inhibited NLRP3 activation, preventing the progression of proteinuria, and renal inflammation and fibrosis in mice. In addition, after UUO surgery, deficiency in Myd88, Nlrp3, Casp1, or Il1r reduced both renal collagen deposition and proteinuria when compared to wild type mice.[13] Oxonic acid-induced hyperuricemia increased renal NLRP3 expression with detachment of renal tubular epithelial cells and interstitial mononuclear cell infiltration in rats.[90]

Furthermore, renal xanthine oxidase activity inhibition by allopurinol reduced the renal sUA levels and ROS production, while inhibiting NLRP3 inflammasome activation and IL-1β expression and attenuating the tubular injury and the development of interstitial inflammation and fibrosis in long term 5/6 renal ablated rats.[91] Similarly, in a model of CKD induced by chronic nitric oxide inhibition associated with salt overload, NLRP3 inflammasome inhibition by allopurinol attenuated hypertension and renal oxidative stress and interstitial inflammation/fibrosis.[92]

Clinical studies have also demonstrated that inhibition of uric acid synthesis exerts beneficial effects in CKD. A 2-year randomized controlled trial demonstrated that treatment with allopurinol prevented the progressive decline in glomerular filtration rate in patients with CKD.[93] In a post-hoc analysis of these patients 5 years later, Goicoechea et al.[94] showed that treatment with allopurinol not only slowed the progression of kidney disease, but also reduced cardiovascular risk. A 3-year randomized parallel-controlled study of patients with type 2 diabetes with asymptomatic hyperuricemia demonstrated similar renal protection by allopurinol treatment.[95] However, whether the renoprotective effect of allopurinol in human disease involves NLRP3 inflammasome inhibition remains to be elucidated.

Recent evidence suggests that febuxostat, another xanthine oxidase inhibitor, is superior to allopurinol in delaying the loss of renal function in patients with CKD and hyperuricemia.[96] In oxonic acid-induced hyperuricemic rats, febuxostat reduced serum uric acid levels and renal cortex expression of NLRP3/IL-1β and alleviated renal damages.[97] In vitro, febuxostat decreased NLRP3 inflammasome-mediated IL-1β secretion by activated macrophages and cell death, and this protective effect was associated with the improvement of the mitochondrial energetics.[98] However, in patients with gout, febuxostat was associated with an increased risk of cardiovascular events and death compared with that associated with allopurinol use,[99] although this effect has not been unequivocally determined.

Up to now, the treatment of hyperuricemic-related diseases requires two complementary approaches: one aimed at lowering levels of uric acid and, the other, at reducing inflammation. Different studies evaluated the possible role of uric acid blockage through the use of xanthine inhibitors, as stated above. The vast majority of these studies have been conducted with allopurinol or febuxostat.[100–103] Lifestyle and socioeconomic changes that occurred over time have resulted in a marked reduction of physical activity, an increased number of psychological stressors and in profound dietary changes.[104] These changes correlate with increased rates of metabolic diseases such as obesity, atherosclerosis, and gout, all of which are triggered by overly active innate immune functions. The chronic inflammation associated with these diseases are termed 'metaflammation' and they contribute to the development of many prevalent noncommunicable diseases, representing a rising public health problem with global epidemic dimensions.[105] The most recent findings point to NLRP3 as a target molecule involved in metaflammation.[106] Treatment targeting the reduction of metaflammation relies on IL-1β blockage, either with antagonist antibodies or IL-1β receptor inhibitors.[59] However, given the complexity and plasticity of the hyperuricemic-associated diseases, anti-IL-1 drugs have not been tested in large numbers of patients, and their use must consider pathogen infections and other comorbidities before being prescribed.

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