A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster

SummaryElevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumulation of UA concretions and diet-dependent shortening of lifespan. Inhibition of insulin-like signaling (ILS) pathway genes reduced UA and concretion load. In humans, SNPs in the ILS genes AKT2 and FOXO3 were associated with UA levels or gout, supporting a conserved role for ILS in modulating UA metabolism. Downstream of the ILS pathway UA pathogenicity was mediated partly by NADPH Oxidase, whose inhibition attenuated the reduced lifespan and concretion accumulation. Thus, genes in the ILS pathway represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones.HighlightsIn Drosophila high uric acid (UA) levels shorten lifespan and cause UA aggregationConserved in flies and humans, the ILS pathway associates with UA pathologiesFoxO dampens concretion formation by reducing UA levels and ROS formationInhibition of NOX alleviates the lifespan attenuation and UA aggregation