Decreased extra-renal urate excretion is a common cause of hyperuricemia

Abstract

ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes—'extra-renal urate underexcretion' and genuine 'urate overproduction'—providing a new concept valuable for the treatment of hyperuricemia and gout.

Rosehip inhibits xanthine oxidase activity and reduces serum urate levels in a mouse model of hyperuricemia

“…However, uricase was lost in hominoids during primate evolution (25). To mimic the purine metabolism of humans who lack uricase, mice were exposed to PO, a uricase inhibitor (30)(31)(32)(33). In the current study, the oral administration of hot water extract was selected in hyperuricemic mice, as rosehip has typically been used for herbal tea and this extract had a high yield when compared with extracts from other extraction methods.…”

“…Treatment of hyperuricemia model mice with rosehip hot water extracts and allopurinol PO, a uricase inhibitor, was used to establish the hyperuricemia model mice, as described previously (30)(31)(32)(33). Briefly, pellet chow and water supplies to the ddY mice (age, 6 weeks; body weight, 31.0±0.37 g) were halted the night before the experiment.…”

“…The imbalance of its production and excretion induces hyperuricemia, which also develops into gout and kidney stones, and accelerates the progression of renal and cardiovascular (28,29). Potassium oxonate (PO)-treated mice generally serve as a model of urate overproduction (hyperuricemia), as its intraperitoneal injection induces the overproduction of urate in mice (30)(31)(32)(33). Indeed, a previous study using PO-treated ABCG2-knockout mice reported that a decrease of extra-renal urate excretion was one of the most common causes of hyperuricemia (33).…”

“…Potassium oxonate (PO)-treated mice generally serve as a model of urate overproduction (hyperuricemia), as its intraperitoneal injection induces the overproduction of urate in mice (30)(31)(32)(33). Indeed, a previous study using PO-treated ABCG2-knockout mice reported that a decrease of extra-renal urate excretion was one of the most common causes of hyperuricemia (33). Numerous studies have demonstrated that the simultaneous administration of a food or beverage that inhibits drug-metabolizing enzymes, such as cytochrome P450 (CYP), and a drug that is metabolized by said enzyme alters blood concentrations, although occasionally with adverse effects (34).…”

Uric acid transporters hiding in the intestine

“…In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of an ABCG2 inhibitor (Hosomi et al 2012). ABCG2 knockout mice significantly exhibited a reduction of intestinal uric acid excretion and an increased plasma concentration of uric acid (Ichida et al 2012). In the 5/6 nephrectomy rat model of chronic kidney disease, serum UA did not increase despite the decrease in UA excretion.…”