Isorhamnetin ameliorates hyperuricemia by regulating uric acid metabolism and alleviates renal inflammation through the PI3K/AKT/NF-κB signaling pathway

Abstract

Hyperuricemia is a chronic metabolic disease with high incidence, and it has become a severe health risk in modern times. Isorhamnetin is a natural flavonoid found in a variety of plants, especially fruits such as buckthorn. The in vivo hyperuricemia ameliorating effect of isorhamnetin and the specific molecular mechanism were profoundly investigated using a hyperuricemia mouse model in this study. Results indicated that isorhamnetin showed a significant uric acid-lowering effect in mice. Isorhamnetin was able to reduce uric acid production by inhibiting XOD activity. Furthermore, it reduced the expression of GLUT9 to inhibit uric acid reabsorption and enhanced the expression of ABCG2, OAT1, and OAT3 to promote uric acid excretion. Metabolomics analysis revealed that gavage administration of isorhamnetin restored purine metabolism and riboflavin metabolism disorders and thus significantly alleviated hyperuricemia in mice. Furthermore, the alleviating effect of isorhamnetin on hyperuricemia-induced renal inflammation and its specific mechanism were explored through network pharmacology and molecular validation experiments. Network pharmacology predicted that seven targets were enriched in the PI3K/AKT pathway (CDK6, SYK, KDR, RELA, PIK3CG, IGF1R, and MCL1) and four targets were enriched in the NF-κB pathway (SYK, PARP1, PTGS2, and RELA). Western blot analysis validated that isorhamnetin inhibited the phosphorylation of PI3K and AKT and down-regulated the expression of NF-κB p65. It indicated that isorhamnetin could inhibit the PI3K/AKT/NF-κB signaling pathway to reduce the levels of renal inflammatory factors (TNF-α, IL-β and IL-6) and ultimately ameliorate hyperuricemia-induced renal inflammation in mice. This study provides a comprehensive and strong theoretical basis for the application of isorhamnetin in the field of functional foods or dietary supplements to improve hyperuricemia.