A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy.

Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (Uox) mouse using the Cre/loxP gene targeting system. These Uox mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the Uox mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in Uox mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old Uox mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, Uox mice are a stable model of human hyperuricemia. Activated DNPB in the Uox mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.