hURAT1 Transgenic Mouse Model for Evaluating Targeted Urate‐Lowering Agents

BACKGROUND: Urate transporter 1 (URAT1) is a well-known therapeutic target for reducing urate levels in the treatment of hyperuricemia and gout. However, current pharmacological studies have failed to evaluate the efficacy of URAT1 inhibitors in non-primate animal models. We established a human URAT1 (hURAT1) transgenic knock-in (KI) mouse model to assess uricosuric agents' effectiveness and characterize URAT1-caused pathogenesis. METHODS: We generated hURAT1 transgenic mice using CRISPR/Cas9 KI technique. mUrat1 knockout was achieved by replacing exon 1 coding sequence with a human SLC22A12 coding sequence (CDS)-pA cassette. Based on the above transgenic mice, a hyperuricemia model was further established by hypoxanthine administration. RESULTS: The hURAT1-KI mice successfully expressed hURAT1 protein to the apical side of the kidney proximal tubule epithelium, where native human URAT1 is localized in human kidney. Upon hypoxanthine challenge, the blood uric acid (UA) level was elevated in hURAT1-KI mice (251 μmol/L), showing an approximately 37% increase compared to wild-type (WT) mice (183.5 μmol/L). The elevated blood UA level could be alleviated by hURAT1 inhibitor benzbromarone treatment in the hURAT1-KI mice (164.2 μmol/L vs. 251 μmol/L, p < 0.05) whereas no response was observed in WT littermates (168.8 μmol/L vs. 183.5 μmol/L). CONCLUSION: The hURAT1-KI hyperuricemia mouse model would be valuable for preclinical evaluation of gout treatment with urate-lowering drugs and for studying UA metabolic complexities in humans.