Abstract: BACKGROUND: Hyperuricemia can induce kidney damage and activate inflammatory signaling pathways, leading to glomerular hypertrophy and the deterioration of renal function. Exercise, as a non-pharmacological treatment method, can regulate the expression of proteins related to uric acid excretion. However, the regulatory mechanism of exercise on hyperuricemia remains unclear.
OBJECTIVE: To explore the potential effect and molecular mechanism of moderate-intensity exercise on hyperuricemia.
METHODS: (1) Using the Mendelian randomization analysis method, the moderate-intensity exercise datasets (ukb-a-508, ukb-b-4710) from the database developed by the MRC Integrative Epidemiology Unit at the University of Bristol were used as the exposure factors, and the serum uric acid level dataset (ebi-a-GCST90018977) was used as the outcome indicator. Meanwhile, the gout datasets (finn-b-GOUT, finn-b-M13GOUT) from the FinnGen, a genomics and personalized medicine research project in Finland, were included as another outcome indicator to explore the potential associations among moderate-intensity exercise, gout, and uric acid levels. (2) An animal experiment was conducted to explore the specific mechanism between moderate-intensity exercise and hyperuricemia. Four groups were set up: blank control group, moderate- intensity exercise + blank group, hyperuricemia model group, and moderate-intensity exercise + hyperuricemia model group. After 8 weeks of moderate-intensity treadmill training in the experimental C57BL/6 mice, biochemical indicators such as serum uric acid, creatinine, and blood urea nitrogen were detected. Hematoxylin-eosin staining was used to observe the pathological changes in kidney tissues. Additionally, qRT-PCR and western blot techniques were employed to analyze the gene and protein expression levels of Nod-like receptor family pyrin domain containing-3, Caspase-1, interleukin-1β, interleukin-6, and interleukin-11.
RESULTS AND CONCLUSION: (1) The results of Mendelian randomization showed that there was a significant negative correlation between moderate-intensity exercise and both gout and serum uric acid level (P < 0.05). (2) Compared with the blank control group, the levels of serum uric acid, creatinine, and blood urea nitrogen in the hyperuricemia model group increased significantly (P < 0.05). (3) Compared with the blank control group, the hyperuricemia model group had pathological changes such as glomerular hypertrophy, vacuolar degeneration of renal tubular epithelial cells, and infiltration of inflammatory cells. (4) Compared with the blank control group, the mRNA expression levels of Nod-like receptor family pyrin domain containing-3, interleukin-1β, and interleukin-18 and the expression levels of Nod-like receptor family pyrin domain containing-3, Caspase-1, interleukin-1β, interleukin-6, and interleukin-11 in the hyperuricemia model group were significantly upregulated (P < 0.05). (5) After moderate-intensity exercise intervention, the above detection indices in the moderate-intensity exercise + hyperuricemia model group decreased significantly (P < 0.05), and the morphology of the renal tissue was improved. These findings suggest that moderate-intensity exercise can reduce the uric acid level and renal injury in hyperuricemia mice. In addition, moderate-intensity exercise can inhibit the activation of the Nod-like receptor family pyrin domain containing-3 signaling pathway and alleviate kidney inflammation.

Key words: hyperuricemia, moderate-intensity exercise, Nod-like receptor family pyrin domain containing-3 (NLRP3) inflammasome, inflammatory response, renal function