Abstract
Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro, DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.
Highlights
Hyperuricemia (HUA), a common extensive metabolic disease, is most commonly caused by excessive production and/or inadequate excretion of uric acid (UA) (Liang et al, 2019)
Mouse primers for apoptosisassociated speck-like (ASC), caspase-1, NOD-like receptor 3 (NLRP3), IL-1β, Urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and xanthine oxidase (XOD) were purchased from Shanghai Sangon Biological Engineering Co., Ltd (Shanghai, China)
Consistent with previous reports, we found that UA levels were observably increased after 7 days of HX and potassium oxonate (PO) co-administration, which indicated the successful construction of HUA model
Summary
Hyperuricemia (HUA), a common extensive metabolic disease, is most commonly caused by excessive production and/or inadequate excretion of uric acid (UA) (Liang et al, 2019). It is well known that hyperuricemia is a potential risk factor for gout and has become an independent risk of multiple metabolic disorders including diabetes (Lv et al, 2013), hypertension (De Becker et al, 2019), atherosclerosis (Liu Z. et al, 2016), and renal disease (Rodenbach et al, 2015). The prevalence of hyperuricemia and gout has risen globally as a result of overconsumption of purine-rich foods. Hyperuricemia has emerged as a serious public health issue that seriously affects the life of patients and leads to the serious social financial burden, which deserves global concern
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