Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models

Abstract

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were 2 aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1^RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1^RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight and cyst index. Mechanisms of increased cyst growth that were investigated were pro-inflammatory cytokines, the inflammasome and crystal deposition in the kidney. Oxonic acid resulted in an increase in pro-inflammatory cytokines in the serum and kidney in Pkd1^RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1^RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1^RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.