Naringenin Ameliorates Hyperuricemia by Regulating Renal Uric Acid Excretion via the PI3K/AKT Signaling Pathway and Renal Inflammation through the NF-κB Signaling Pathway

Abstract

Hyperuricemia characterized by high serum levels of uric acid (UA, >6.8 mg/dL) is regarded as a common chronic metabolic disease. When used as a food supplement, naringenin might have various pharmacological activities, including antioxidant, free-radical-scavenging, and inflammation-suppressing activities. However, the effects of naringenin on hyperuricemia and renal inflammation and the underlying mechanisms remain to be elucidated. Here, we comprehensively examined the effects of naringenin on hyperuricemia and the attenuation of renal impairment. Mice were injected with 250 mg/kg of potassium oxonate (PO) and given 5% fructose water to induce hyperuricemia. The pharmacological effects of naringenin (10 and 50 mg/kg) and benzbromarone (positive control group, 20 mg/kg) on hyperuricemic mice were evaluated in vivo. The disordered expression of urate transporters in HK-2 cells was stimulated by 8 mg/dL UA, which was used to determine the mechanisms underlying the effects of naringenin in vitro. Naringenin markedly reduced the serum UA level in a dose-dependent manner and improved renal dysfunction. Moreover, the increased elimination of UA in urine showed that the effects of naringenin were associated with the regulation of renal excretion. Further examination indicated that naringenin reduced the expression of GLUT9 by inhibiting the PI3K/AKT signaling pathway and reinforced the expression of ABCG2 by increasing the abundance of PDZK1 in vivo and in vitro. Furthermore, sirius red staining and western blotting indicated that naringenin plays a protective role in renal injury by suppressing increases in the levels of proinflammatory cytokines, including IL-6 and TNF-α, which contribute to the inhibition of the TLR4/NF-κB signaling pathway in vivo and in vitro. Naringenin supplementation might be a potential therapeutic strategy to ameliorate hyperuricemia by promoting UA excretion in the kidney and attenuating the inflammatory response by decreasing the release of inflammatory cytokines. This study shows that naringenin could be used as a functional food or dietary supplement for hyperuricemia prevention and treatment.

Coffee Leaf Tea Extracts Improve Hyperuricemia Nephropathy and Its Associated Negative Effect in Gut Microbiota and Amino Acid Metabolism in Rats

“…Once these transporters are dysfunctional, the uric acid metabolic system will be disrupted, contributing to hyperuricemia. 31 In this study, TE showed an XOD inhibitory effect in HN rats and reversed the dysregulated expression of the uric acid transporters. Consistently, TE promoted the excretion of uric acid.…”

“…Uric acid transporters such as GLUT9, OAT3, and ABCG2 are commonly located in the human intestine and the renal proximal tubule. Once these transporters are dysfunctional, the uric acid metabolic system will be disrupted, contributing to hyperuricemia . In this study, TE showed an XOD inhibitory effect in HN rats and reversed the dysregulated expression of the uric acid transporters.…”

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

“…This process is referred to as lipid raft-dependent redox signaling, which profoundly affects cell physiopathology in various mammalian cells . Naringenin can inhibit TLR4/NF-κB and effectively alleviate the inflammatory response, which shows a protective role in the gut. − Here, we provide evidence that the modulation of TLR4/NF-κB by naringenin requires subcellular TLR4 translocation, which is also controlled by lipid raft redox signaling. Therefore, our findings indicate that the lipid raft is a key point and is part of a highly important signaling mechanism that is involved in naringenin-mediated regulation of antioxidation and anti-inflammatory activities.…”

Effect of ferulic acid and p‐coumaric acid on lowering uric acid through network pharmacology and in vitro studies

“…UA excretion occurs mainly in the kidney and to a lesser extent in the intestine through metabolism by intestinal bacteria (Yang et al., 2023). The renal excretion pathway of UA consists of four main components, namely filtration‐reabsorption‐secretion‐post‐secretion reabsorption.…”