Abstract
High uric acid is associated with gout, hypertension, metabolic syndrome, cardiovascular disease, and kidney disease. URAT1 (SLC22A12), originally discovered in mice as Rst, is generally considered a very selective uric acid transporter compared to other closely-related kidney uric acid transporters such as OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8). While the role of URAT1 in regulating human uric acid is well-established, in recent studies the gene has been linked to redox regulation in flies as well as progression of renal cell carcinoma. We have now identified over twenty metabolites in the Urat1 knockout that are generally distinct from metabolites accumulating in the Oat1 and Oat3 knockout mice, with distinct molecular properties as revealed by chemoinformatics and machine learning analysis. These metabolites are involved in seemingly disparate aspects of cellular metabolism, including pyrimidine, fatty acid, and amino acid metabolism. However, through integrative systems metabolic analysis of the transcriptomic and metabolomic data using a human metabolic reconstruction to build metabolic genome-scale models (GEMs), the cellular response to loss of Urat1/Rst revealed compensatory processes related to reactive oxygen species handling and maintaining redox state balances via Vitamin C metabolism and cofactor charging reactions. These observations are consistent with the increasingly appreciated role of the antioxidant properties of uric acid. Collectively, the results highlight the role of Urat1/Rst as a transporter strongly tied to maintaining redox homeostasis, with implications for metabolic side effects from drugs that block its function.