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

Abstract

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 Uoxmice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the Uoxmice 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 Uoxmice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old Uoxmice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, Uoxmice are a stable model of human hyperuricemia. Activated DNPB in the Uoxmice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.